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The uses of radiotracers in the life sciences

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2009 Rep. Prog. Phys. 72 016701

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IOP PUBLISHING REPORTS ON PROGRESS IN PHYSICS
Rep. Prog. Phys. 72 (2009) 016701 (23pp) doi:10.1088/0034-4885/72/1/016701

The uses of radiotracers in the life sciences

Thomas J Ruth
TRIUMF, Vancouver, Canada

Received 1 August 2007, in final form 27 October 2008

Published 16 December 2008
Online at stacks.iop.org/RoPP/72/016701

Abstract
Radionuclides have been used to follow physical, chemical and biological processes almost
from the time of their discovery. Probably the application with the biggest impact has been in
the medical field where radionuclides have been incorporated into biologically active
molecules and used to diagnose a wide variety of diseases and to treat many disorders. Other
uses in the life sciences, in general, are related to using a radioactive isotope as marker for an
existing species such as nitrogen-13 in plant studies or copper-67 to track copper catalysts in
phytoplankton.
This review describes in general terms these uses as well as providing the reader with the
background related to the physical properties of radioactive decay, the concepts associated
with the production of radionuclides using reactors or accelerators and the fundamentals of
imaging radioactivity. The advances in imaging technology in recent years has had a profound
impact on the use of radionuclides in positron emission tomography and the coupling of other
imaging modalities to provide very precise insights into human disease.
The variety of uses for radiotracers in science is almost boundless dependent only upon
ones imagination.
(Some figures in this article are in colour only in the electronic version)
This article was invited by Professor G Gillies.

Contents
1. Introduction 1 4.5. Radionuclides for therapy 15
2. Radioisotope/radionuclide production 2 5. Radiopharmaceuticals 17
2.1. Specific activity 3 6. Environmental/biological applications 17
2.2. Reactors 3 6.1. Agricultural applications 17
2.3. Cyclotrons 4 6.2. Plant physiology 18
2.4. Generators 6
6.3. Earth and ocean sciences 18
3. Radioactive tracers 6
4. Medical applications 7 6.4. Insect control 18
4.1. Historical background 7 6.5. Water resources 18
4.2. Radioimmunoassay 8 7. Concluding remarks 18
4.3. Radiotracers in medicine—ex vivo applications 8 Acknowledgments 20
4.4. Imaging 8 References 20

1. Introduction powering common household items, to producing electricity

for one of every five US homes and businesses.
Just as early man harnessed fire to improve his life, society The first practical application of a radioisotope was made
in the last century was able to harness radiation. The by George de Hevesy in 1911. At the time, de Hevesy
development of nuclear technology is one of the most was a young Hungarian student working in Manchester with
significant achievements of the 20th century. Today nuclear naturally radioactive materials. Not having much money he
technology is used in nearly every field and aspect of our lived in a boarding house and took his meals there with his
lives—from medicine, to manufacturing and construction, to fellow boarders. He began to suspect that some of the meals

0034-4885/09/016701+23$90.00 1 © 2009 IOP Publishing Ltd Printed in the UK

Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

might be made from leftovers from the preceding days or 140 keV). In addition, the ease with which an iodine atom
even weeks, but he could never be sure. To try and confirm can be inserted into a compound makes 123 I extremely
his suspicions de Hevesy put a small amount of radioactive versatile as a radiotracer in SPECT (Lambrecht et al 1972,
material into the remains of a meal. Several days later when the Kulkarni 1991, Kung et al 2003).
same dish was served again he used a simple radiation detection Rhenium-186 is a β − emitter with a low abundant
instrument—a gold leaf electroscope—to check whether the γ -ray with an energy of 137 keV. The 1 MeV (maximum
food was radioactive. It was, and de Hevesy’s suspicions
energy) β − -rays and its 90 h half-life make it a
were confirmed. This anecdotal story illustrates the inquisitive
promising radiotoxic nuclide for therapy. As an
approach de Hevesy took in solving a personal dilemma
analog of technetium, rhenium possesses similar chemical
while in fact he was heavily involved in his research using
properties and can thus be used to label some of the
radioactivity to trace lead (Levi 1976).
same compounds that have been previously developed for
The use of radionuclides in the physical and biological
sciences can be considered tracer science with special imaging tumors (Maxon et al 1990, Kolesnikov-Gauthier
application to medicine where they are used for imaging and et al 2000).
radiotherapy. Imaging can be further subdivided into planar
Most of the radiotracers have relatively short half-lives
imaging, positron emission tomography (PET) and single
photon emission computed tomography (SPECT). All of these (from less than a few hours to at most a few days). There
uses rely on the fact that the radionuclides are used at very are definite advantages in using short-lived radionuclides. For
low concentration. In order to be used in this manner the example, there is a low radiation dose associated with each
radionuclides and the compounds to which they are attached study, serial studies are possible (sometimes on the same day
must obey the three tracer principles. These state that for tracers such as 11 C) and the radioactive waste disposal
problems are minimized if not eliminated. The disadvantages
• the tracer behaves or interacts with the system to be probed include the need for an accelerator or other source nearby
in a known, reproducible fashion,
or within easy shipping distance for the longer lived species
• the tracer does not alter or perturb the system in any
and rapid chemical procedures, especially for more complex
measurable fashion and
compound formation.
• the tracer concentration can be measured.
Throughout the rest of this paper, examples of the
In radiotherapy, the second principle is, in a strict sense, application of radioactive tracers will be provided in some
broken since the point of delivering the radiotoxic substance is detail and the high sensitivity of the techniques will be
to have the emitted radiation cause damage to the undesirable illustrated.
surrounding tissues. However, in order for the radiotoxic
substance to localize in sufficient quantities it must follow
the known chemical behavior without perturbing that pathway, 2. Radioisotope/radionuclide production
and thus behave like a tracer. When radiotracers are used for
diagnostic or therapeutic purposes, imaging and radiotherapy, Radionuclide production is indeed true alchemy, that is,
respectively, they are referred to as radiopharmaceuticals
converting the atoms of one element into those of another.
since they must be of pharmaceutical quality for human use.
This conversion involves altering the number of protons and/or
Radiopharmaceuticals will be discussed further later.
neutrons in the nucleus (target). If a neutron is added without
The following are some typical radionuclides used in each
the emission of proton(s) then the resulting nuclide will have
of the broad categories.
the same chemical properties as the target nuclide—differing
Carbon-11 is a positron emitting radionuclide with a half- only in mass. If, however, the target nucleus is bombarded
life of 20.3 min. It is generally produced as 11 CO2 which by a charged particle, for example, a proton, the resulting
can be converted into a wide variety of labeling agents nucleus will usually be that of a different element. The exact
such as 11 CH3 I or H11 CN. Since carbon is a constituent type of nuclear reactions that a target undergoes depends on
of all biological compounds, 11 C finds widespread use as the number of parameters including the type of bombarding
a tracer in PET. In fact, more than 200 compounds have particle and the energy of this projectile.
been labeled with C-11 (Iwata 2002).
The binding energy per nucleon in the nucleus is on the
Nitrogen-13 is also a positron emitting radionuclide.
order of 8 MeV. Therefore, if the incoming projectile has more
However, in addition to its use as a cardiac blood flow
agent (in the form of 13 NH+4 ) it is used in applications than this amount of energy, the resulting reaction will cause
other than PET imaging. For example, it is widely used in other particles to be ejected from the target nucleus. By
botany studies to determine the kinetics of nitrogen uptake carefully selecting the target nucleus, the bombarding particle
in a variety of plant systems under a variety of conditions and its energy, it is possible to produce a specific radionuclide.
(Bingham 2000, Glass 2002). Detailed examples will be Figure 1 illustrates the various exit routes from the production
discussed in section 6. of the compound nucleus generated by bombarding nitrogen-
Iodine-123 emits γ -rays with an energy of 159 keV. This 14 with protons.
is ideally suited for imaging in SPECT cameras, as they A more complete description of the process of
have been optimized for use with 99m Tc (γ -ray energy = radionuclide production is given below.

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

99
Mo

235 236
U U

Neutron

135
Sn

Figure 1. Schematic illustration of the possible nuclear reactions

from the bombardment of N-14 with protons. The relative amounts Figure 2. Schematic of the fission process following neutron
of each of the product nuclei will depend upon the energy of the capture by U-235. The unstable compound nucleus breaks into 2
incoming proton. fragments with a distribution as shown in figure 3. Between 2 and 3
neutrons accompany the breakup of the compound nucleus.

2.1. Specific activity

9.3 × 109 Ci mol−1 . In SI units we have 340 exabecquerels per
Specific activity is a measure of the number of radioactive mole (3.4 × 1020 Bq mol−1 ).
atoms or molecules as compared with the total number of those If the substance had instead been 14 C-labeled with its
atoms or molecules present in the sample. The specific activity 5715 y half-life, then following the same process, but using
is usually expressed in terms of radiation units per mass unit. the decay constant (λ = 3.84 × 10−12 s−1 ) for 14 C, the
The traditional units have been Ci mol−1 (Ci g−1 ) or a fraction resulting specific activity would be 6.2 × 104 mCi mol−1 or
thereof (now expressed in SI units as GBq mol−1 ). If there 62 CIF mol−1 . If the radiolabeled glucose had been prepared
are no stable or radioactive contaminants of the same element, in a growing plant, the naturally occurring glucose would have
then the sample is referred to as carrier free. For example, lowered the SA due to the non-radioactive glucose molecules.
a compound labeled with 211 At will be carrier free since there Therefore, it is easy to see that short-lived radioisotopes have
are no stable isotopes of astatine (assuming, of course, that the potential for much higher specific activity but this also
there are no other radioisotopes of astatine present). depends upon the chemical purity.
However, in most cases there are small quantities of
unlabeled compounds that have a similar chemical behavior 2.2. Reactors
and can act as pseudo-carrier. By pseudo-carrier it is meant
that while there may not be true isotopic species present, the Following the Second World War reactors began to be used for
molecules co-existing with the compound in question possess a number of research areas including radionuclide production.
similar chemical behavior and thus represents a contamination. The use of nuclear reactors for the production of radionuclides
The specific activity of an isotope or radiopharmaceutical is relies on the fact that during the fission process in a reactor,
important in determining the chemical/biological effect the there are large numbers of neutrons produced with a wide
substance may have on the system under investigation. range of energies. These neutrons can be used directly or
The number of radioactive atoms, N , in a sample can be thermalized (slowed) by the surrounding media. The term
calculated from the relationship of radioactivity to quantity of thermal neutron means they have kinetic energy associated
material present and expressed as with room temperature (about 0.025 eV). These thermalized
neutrons are ideal for initiating (n,γ ) reactions. In some
dN/dt = −λN, (1) reactors, higher energy or fast neutrons (>1 MeV) are used to
produce radioisotopes via other reactions, for example, (n,p)
where dN/dt is the disintegration rate per second, while λ is or (n,α) reactions. Figure 2 illustrates the fission process.
the decay constant in reciprocal seconds (λ = ln(2)/t1/2 ). The fission process is a source of a number of widely
As an example of specific activity assume that glucose has used radionuclides. For example, 90 Sr, 99 Mo, 131 I and 133 Xe
been labeled with 10 mCi of C-11 with a half-life of 20.3 min. are all produced in reactors by fission and can be separated
Its carrier free specific activity would be obtained by first from uranium fuel cells or from targets of enriched 235 U
determining the number of 11 C atoms: placed in the reactor for radionuclide production directly.

 The distribution of isotopes (both radioactive and stable) is
− dN (10 mCi)(3.7 × 107 dps mCi−1 )
N11 C = dt =   illustrated in figure 3. The peak of the lower mass is at mass
λ ln(2)
99 which includes Mo-99. Approximately 6% of all fissions
(20.3 min)(60 s min−1 )
yield Mo-99; thus the fission approach is a very efficient mode
= 6.5 × 1011 atoms. of production for this important radionuclide.
Using Avogadro’s number, the number of moles is then The major drawbacks from using fission produced
1.08 × 10−12 . Dividing the amount of radioactivity by the materials are the large quantities of radioactive waste material
number of moles we have 9.3 × 1012 mCi mol−1 or a SA = generated and the large amounts of radionuclides produced

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Table 1. The most commonly used positron emitters and typical

reactions for their production.
Decay Energy
Radionuclide t1/2 mode Reaction (MeV)
11
C 20.3 min β+ 14
N(p,α) 11–17
13
N 9.97 min β+ 16
O(p,α) 19
13
C(p,n)a 11
15
O 2.03 min β+ 15
N(p,n)a 11
14
N(d,2n) 6
16
O(p,pn) >26
18
F 110 min β+ 18
O(p,n)a 11–17
nat
Ne(d,α) 8–14
a
These reactions required enriched target material.

disrupt the neutron flux. Typically only longer lived (>1 d)

radionuclides are produced in reactors. In addition, as very
few new reactors are being built, the availability of this
source of radionuclides for medical and scientific endeavors
is diminishing1 .

2.3. Cyclotrons
It is ironic that the first artificially produced radionuclides
were created on Lawrence’s cyclotrons (Lawrence and
Livingston 1932, Lawrence 1940), but it took another 30
years before accelerator produced radionuclides began to
Figure 3. The two curves show the asymmetric yield distribution of
radioisotopes as a function of atomic mass from the fission of U-235 play a major role in the production of medically important
(solid curve) and from Pu-239 (dashed curve). Note that the yield radiopharmaceuticals. The principal advantage of accelerator
peaks on the lower mass hump at mass equal to 99. This is why produced radionuclides is the high specific activities that can
reactor production of Mo-99 is so favorable (C C Lin, be obtained through the (p,xn) and (p,α) reactions that result
Radiochemistry in Nuclear Power Reactors, National Academy in the product being a different element from the target.
Press (1996)).
Another significant advantage is that a smaller amount of
radioactive waste is generated from charged particle reactions
in comparison with reactor production.
including isotopes of the desired species. The co-produced
Cyclotrons used for producing medical radionuclides were
radionuclides become a radioactive waste issue if other uses
initially designed for physics experiments and used only part
cannot be identified. In producing 131 I from fission, the
time for medical applications. These cyclotrons were capable
isotopes 127 I and 129 I are also formed, thus reducing the specific
of accelerating protons, deuterons, 3 He+2 and α-particles (the
activity. Since 131 I is obtained from the decay of 131 Te, neutron
nucleus of 4 He). As can be seen from table 1 however,
capture on enriched 130 Te is utilized to produce the required
131 the PET radionuclides are produced from either proton or
Te. As such, the isotopic purity of the 131 I is directly related
deuteron reactions. In the early 1980s, small compact proton-
to the level of enrichment of the target material, 130 Te. 131 I
only cyclotrons became available and cyclotrons specifically
is then extracted from the tellurium oxide via dry distillation
designed for producing PET radionuclides were installed in a
at around 600–650 ◦ C. This is an analogous approach to that
which is used to extract 123,124 I from cyclotron irradiated targets few hospitals.
of 124 Te. The principle of the cyclotron is based on the application
Because 235 U enrichment above 20% constitutes weapons of small accelerating voltages repeatedly. Figure 4 shows the
grade material (typically the enrichment is as high as 93% principal components of a cyclotron. Hollow cavities called
235
U), there is growing concern regarding its use for the dees because of their shape serve as the electrodes for the
production of medical radionuclides. While there are acceleration. A radiofrequency (RF) oscillator is connected
processes in place for the use of lower enrichment (which to the dees such that the electrical potential on the dees is
means dealing with larger waste streams) the major producers alternatively positive and negative with respect to each other.
have not switched over as of 2008. By placing the dees between the poles of a strong magnet so
Reactor production offers some advantages in that that the magnet field is perpendicular to the plane of motion,
production is carried out in a passive mode. That is, in the the charged particle undergoing acceleration will move in a
presence of neutrons, the targets are inserted and withdrawn circular path. As the particle gains energy it moves in a
throughout an operational cycle. Insertions and withdrawals 1 For further reading see IAEA TECDOC 1340 ‘Manual for Reactor Produced

are performed under controlled conditions, so as to not greatly Radioisotopes’.

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

vacuum tank, magnet, ion source, extraction system) there have

been some innovations in the last few decades that have had a
major impact on the design of the modern cyclotron. The two
most significant changes have occurred in getting the ions into
the cyclotron (ion source) and out of the cyclotron (extraction
system).
Nearly all modern cyclotrons now use a negative ion
source. Ions are generated by passing the source gas through
an electric field that generates negative and positive ions (e.g.
in the case of H2 , the resulting ions will be H+ or protons and
H− ions, a proton with 2 electrons). The advantage of negative
ions resides in the ability to easily have a variable energy
cyclotron, to have nearly 100% extraction (see below) and to be
able to extract multiple beams, simultaneously. The design of
the ion source has also changed in that the ion source can reside
inside the cyclotron where the ions are generated at the center of
the cyclotron (central region) or from outside of the cyclotron
Figure 4. Photograph of the interior of a cyclotron shows the copper (external ion source) and subsequently injected into the central
‘dees’, the accelerating component of a cyclotron and the 4 ‘hills’ of
the steel magnet. This cavity is enclosed with a plate so that a region for acceleration. There are obviously advantages and
chamber capable of sustaining a vacuum is formed. Ions of a light disadvantages to each approach. With an external ion source
particle such as hydrogen or helium are injected into the center of the vacuum can be operated at very low pressures with very
the cyclotron where they are accelerated by the electrically charged little beam loss due to stripping of the negative ion by the
dees. The dees are high voltage cavities that change polarity
residual gas. However, the vacuum system must be of a very
(electrical charge) at a high frequency (radiofrequency—tens of
megahertz). The magnet forces the charged particles to move in a clean nature to maintain this high vacuum. With an external
circular path. As the particle gains energy the circular path increases ion source, maintenance can be performed without opening the
in radius until it reaches the energy desired whereupon it is extracted cyclotron or breaking vacuum. In addition the central region
and directed to a target material where a nuclear reaction forms the is not disturbed as in the case of the internal ion source that is
radionuclide of choice. (Photo of TRIUMF TR13 cyclotron.)
part of the central region.
The simplicity of the design for proton-only cyclotrons
resulted in cyclotrons which accelerate H− ions capable of
spiral outward from the center. With the source of negative
two or more simultaneous beams of varying energies and
ions at a point in the center of the cyclotron the positive dee
intensities. The modern cyclotron is completely controlled
will accelerate the ions toward that dee with the magnetic
by a computer and is capable of running for many days with
field forcing them to move in a curved path. Once inside
minimal attention. The major drawback from these proton
the cavity the particles no longer experience an electric force.
cyclotrons lies in the fact that in some cases an enriched target
Continuing in the circular path the particles will exit the dee
material must be used for a sufficient product to be generated.
and enter the gap between the dees where the second dee has
One of the major drawbacks to the widespread availability
changed its potential to be an attracting force, accelerating the
of PET is the high capital cost associated with the cyclotrons
particles to that dee. The dees reverse their potential when
and scanners. However, the success of the small low energy
the particles are inside the dees so that at each crossing of the
cyclotron encouraged research into the design of even lower
gap the particles receive an increase in energy of the order of
energy accelerators, i.e. linear accelerators and cyclotrons of
20–50 keV. Lawrence discovered the equations defining this
principle of operation in 1929 and built the first cyclotron in a few megaelectronvolts extracted energy. To date, there are
1931. very few of these machines in routine use.
Regardless of the type of accelerator used to produce the
Bev = mv 2 /r and r = mv /Be. (2) radionuclides, the production rates depend on the flux of the
bombarding particles, the number of target nuclei and the
Since angular velocity ω = v /r, then probability of the reaction occurring. The equation for the
rate of production is
ω = Be/m, (3) R = I σ t, (4)
where m is the mass of the ion, e is its charge and v its velocity where R is the rate of nuclei formed per second, I is the flux of
with B equaling the magnetic field and r is the radius of the the bombarding particles per second, σ is the cross section
ion’s orbit. Thus the orbit of the particle is directly proportional (probability of the reaction occurring) in cm2 and t is the
to the particle momentum and the particle orbit frequency is target thickness expressed as the number of nuclei per square
constant and independent of energy. This principle breaks centimeter. It is of historical interest to note that the unit for
down under relativistic effects where the mass is not constant. cross section is the barn, which is equivalent to 10−24 cm2 . The
While the basic components of modern cyclotrons are expression ‘barn’ comes from the fact that the probability of a
essentially the same as the original designs (RF cavities, neutron interacting with a target is proportional to the area of

5
Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

the nucleus, which, compared with the size of the neutron, is λd , and the number of radioactive nuclei, N , present (λd N ).
as big as a barn. The first term accounts for the growth of the daughter as a
The rate of production is, of course, affected by the fact function of the decay of the parent as well as the disappearance
that the resulting nuclide is radioactive and thus undergoes of the daughter due to its own decay. The last term accounts
radioactive decay. For short-lived nuclides the competing for the presence of daughter nuclei at zero time.
reaction rates, production and decay will achieve equilibrium All generator systems used routinely in nuclear medicine
at sufficiently long bombardment times since the rate of decay form an equilibrium between parent and daughter radionuclei.
is proportional to the number of radionuclei present. The In the case of the 99 Mo/99m Tc generator, the parent (99 Mo)
point where equilibrium is reached is called saturation. This decays at a rate relatively similar to that of the daughter (99m Tc).
means that there is no benefit to longer irradiations, as the With a half-life of 66 h for 99 Mo versus 6 h for 99m Tc, there is
production rate equals the rate of decay, and therefore no an appreciable decay of the parent before the daughter reaches
additional product will be formed. At shorter irradiation times steady state. This steady state condition is referred to as
the fraction of product produced is related to the saturation transient equilibrium. With transient equilibrium, the daughter
factor given by (1 − e−λt ), where λ is the decay constant of the radioactivity grows in and surpasses that of the parent before
decaying nuclide and t is the bombardment time. It is evident equilibrium is reached. The ratio of the daughter radioactivity
that an irradiation equivalent to one half-life would result in a to that of the parent is given by equation (6),
saturation factor of 50%. For practical reasons, an irradiation
Ad Tp
rarely exceeds three half-lives (90% saturation) except for the = , (6)
shortest-lived radionuclides. Ap Tp − T d
For long lived species, the quantity produced is usually
where T is the half-life for each species, respectively (see
expressed in terms of the integrated dose or the total beam flux figure 5).
(µA h). For example, with a long lived radionuclide such as The useful lifetime of the 99 Mo/99m Tc generator is
82
Sr (t1/2 = 25 d) the amount produced will be essentially the determined by two factors: (1) the amount of 99m Tc that
same whether it is produced from 100 µA in 1 h or 50 µA in can be eluted from the generator in a volume suitable for
2 h (both represent 100 µA h of the beam)2 . use in the diagnostic procedure and (2) the amount of 99 Mo
that is co-eluted or the amount of breakthrough. The US
2.4. Generators Pharmacopeia and the US Nuclear Regulatory Commission
or equivalent Agreement State regulations specify a limit of
Finally, the other source of radionuclides used in medicine
0.00015 MBq molybdenum Mo-99 per MBq of technetium
is the generator. The most widely used generator system is
Tc-99m (0.15 µCi Mo-99/mCi Tc-99m) at the time of
the 99 Mo/99m Tc pair, where over 80% of all nuclear medicine
administration to each patient.
procedures performed worldwide use Tc-99m as the imaging
For the situation where the parent has a half-life much
radionuclide. There are numerous Tc-99m kits for producing
longer than the daughter, e.g. 68 Ge/68 Ga and 82 Sr/82 Rb, the
tracers to examine the brain, kidney, heart, bone, liver, lung,
change in the amount of the parent during the time for steady
red blood cells and TcO− 4 for thyroid. The parent Mo-99 is state to be reached will be negligible; the steady state condition
produced in a reactor, usually as a fission product from U-235.
is referred to as secular equilibrium. The quantity of daughter
A radioactive generator takes advantage of the cases
activity at any time is then expressed by equation (7)
where one longer lived (parent) radionuclide decays, usually
by β − emission, to a shorter lived (daughter) radionuclide. Ad (t) = Ap (0)(1 − e−λd t ). (7)
The chemical differences in the two elements are exploited to
separate the daughter product from the parent. The parent Thus, in secular equilibrium, when e−λdt ≈ 0, the daughter
radionuclide is produced by one of the methods described and parent radioactivity are approximately equal.
above and then attached to an inert substance from which the From table 2, it is easy to see that generators have a
desired product can be eluted or washed off the support. The wide variety of uses and half-lives of both parent and daughter
product can be used directly as in the case of 82 Rb+ from the nuclides. Obviously, from an end user perspective, the long
Sr/Rb generator or after undergoing a chemical reaction in the lived parent makes it possible to have a single generator in use
case of 99m Tc from the Mo/Tc generator (see below). for an extended period of time. The utility of the generator is
The equilibrium equations that reflect the relative actually based primarily on the daughter’s half-life and the
radioactivity of parent and daughter are given by the general chemistry required to provide the radionuclide in a useful
equation: species. The simplest systems make use of the daughter
  nuclide directly; 82 Rb+ and 81m Kr are used directly as a K+
(λd )(e−λp t − e−λd t ) ion analog and as an inert gas ventilation tracer, respectively.
Ad (t) = Ap (0) + Ad (0)e−λd t , (5)
λd − λ p

where A is the radioactivity of the daughter ‘d’ and parent ‘p’,

3. Radioactive tracers
respectively. Ad is equal to the product of the decay constant, In addition to the use of radionuclides in medicine there are
2 For further reading see IAEA TecDoc ‘Theory and Practice of Production a wide variety of uses for following the behavior of system,
of Radioisotopes Using Cyclotrons’ 2007 (at press). both on the large scale such as the environment and a much

6
Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Table 2. Examples of generator systems available today. Activity versus Time, Mo-99 and Tc-99m
10
Parent Daughter
Generator t1/2 t1/2 Uses 9
Mo-99
99
Mo/99m Tc 66 h 6h Tc-99m is the most 8 Tc-99m
widely used radionuclide 7
in nuclear medicine,
single photon emitter 6

Curies
68 68
Ge/ Ga 270 d 68 m In equilibrium as a long 5
lived positron source;
Ga metal chemistry 4
82
Sr/82 Rb 25.5 d 76.4 s Cardiac blood flow 3
188
W/188 Re 69 d 16.9 h Radionuclide therapy
2
(β-particles)
81 81m
Rb/ Kr 4.58 h 13 s Lung ventilation studies 1
225
Ac/213 Bi 10.0 d 45.6 m Radionuclide therapy
0
(α-particles)
62 0 24 48 72 96 120 144 168 192 216 240
Zn/62 Cu 9.26 h 9.7 m Blood flow, hypoxia
Hours

Figure 5. Illustration of the decay of Mo-99 with the in-growth of

smaller scale as in the chemical process in the lab. As Tc-99m.
indicated in the introduction the term radiotracer refers to a
radioactive species that is used to follow (trace) the uptake
into or function of an organ system in a living plant, animal
4. Medical applications
or physical/chemical process. Initially, the radiotracers used
Nuclear medicine makes use of the fact that certain
were radioactive isotopes of naturally occurring elements
radionuclides emit gamma rays with sufficient energy for
as in the case where de Hevesy used radioactivity to trace
detection outside of the body. In attaching such radionuclides
food leftovers in his boarding house (see above). While
to biologically active compounds, the activity will either
early radiotracer applications used simple, naturally occurring
localize within particular bodily tissues or be free to
elements, today the use of radiotracers is based on the
follow a particular biochemical pathway. The radiotracers
production of radionuclides by one of the aforementioned
that are used to study bodily function are referred to as
methods.
radiopharmaceuticals. The term has been used because of
Radioactive isotopes of the elements of sodium and
the similar properties between these tracers and the drugs or
potassium (24 Na, 42 K) have been used as chloride salts to
pharmaceuticals that have been developed to treat disease. The
measure the sodium and potassium content of the body
employing the isotope dilution technique. Analysis by isotope following discussion will concentrate on the uses of radioactive
dilution involves the addition of a known mass and specific substances for the diagnosis of human pathology using imaging
activity of a particular isotope to a mixture containing an as well as by taking samples from blood or exhaled air and in
unknown quantity of that element. An aliquot of the mixture their use for therapeutic treatment.
is then analyzed to determine the new specific activity of the
substance under investigation. It can be shown that the mass, 4.1. Historical background
M, of the substance of interest in the unknown mixture may
Nuclear medicine (NM) has its origins in the pioneering work
be expressed as
  of the Hungarian doctor, G de Hevesy, who, in 1924, used
S1 radioactive isotopes of lead as tracers in bone studies. These
M = M1 −1 , (8)
S2 studies were in addition to his amateur detective work at his
boarding house. Shortly thereafter, Stevens made intravenous
where S1 and S2 are the specific activities of the tracer added
injections of radium chloride to study malignant lymphomas
before and after addition to the system, respectively, and M1
(1926).
is the mass of the spike added to the system.
However, it was not until the discovery of artificially
As an example, suppose the amount of copper in a system
produced radioactive isotopes that the number of available
was to be determined. A spike of copper containing 0.5 mg
species suitable for use as tracers began to increase. The
with 5 kBq of 64 Cu is added to 20 mL of the unknown sample.
After addition and mixing, a portion of the mixture is isolated invention of the cyclotron by Ernest Lawrence in 1932 made
and the specific activity (Bq mg−1 ) of copper is determined. it possible to produce radioactive isotopes of a number of
In this example, say that the analysis yields a S2 value of biologically important elements. The use of these artificially
0.024 kBq mg−1 . Using the above equation the amount of produced radiotracers continued with J G Hamilton and
copper in the unknown sample is R Stone using radioactive sodium clinically in 1937. S Hertz,
A Roberts and R D Evans, in 1938, used radioactive iodine
M = 0.5 mg × ((10 kBq mg−1 /0.024 kBq mg−1 ) − 1)
in the study of thyroid physiology, followed, in 1939, by
= 207 mg of copper. J H Lawrence, K G Scott and L W Tuttle in the study of
This method of isotope dilution has a number of applications, leukemia with radioactive phosphorus. By 1940 J G Hamilton
especially in tracer elemental analyses of living systems. and M H Soley were performing studies in iodine metabolism

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

by the thyroid gland in situ by comparing the use of radioiodine for the unknown and the standards to be chemically identical or
in control subjects to patients with various types of goiters to have identical biological behavior. The original technique
(Harbert and da Roche 1984). has been modified by making use of a variety of radiotracers to
The first medical cyclotron was installed in 1941 at measure concentrations of vitamins, enzymes, peptides, serum
Washington University, St Louis, where radioactive isotopes proteins, hormones, viruses, drugs and tumor antigens (Ruth
of phosphorus, iron, arsenic and sulfur were produced. With 1994).
the development of the fission process during the Second Commercially available kits provide the materials for
World War (WWII), most radionuclides of medical interest performing RIA. A typical kit would consist of a series of
began to be produced in nuclear reactors. After WWII the standard samples each containing a specific amount of an
wide use of radioactive materials in medicine established a unlabeled antigen, a vial of a labeled antigen, a vial of
new field of what was then called atomic medicine and only antibody and a substance used to precipitate the antigen–
later became known as nuclear medicine. Radioactive carbon, antibody complex. In most cases I-125 is the isotope employed
tritium, iodine, iron and chromium found increasing use in the as the radioactive label on the antigen.
study of disease processes.
Ben Cassen, 1951, developed the concept of the rectilinear 4.3. Radiotracers in medicine—ex vivo applications
scanner which opened the way to obtaining the distribution of
radioactivity in a subject within a short time. This was followed In the development of drugs or even biomarkers the use of
by the production of the first gamma camera by Hal Anger in radiotracers labeled with 3 H and 14 C have played an important
1958. The original design was modified shortly afterwards part in determining the biodistribution as a function of time
to what is now known as the Anger scintillation camera, thus after injection and the determination of the pharmacokinetics
heralding the modern era of gamma cameras whose principles of the substances under investigation. These studies involve the
are still in use today. administration of the tracer to a rodent (rat or mouse) and the
sacrificing of the animal at specific time points with the organ of
Powell Richards developed the 99 Mo/99m Tc generator
interest excised for further analysis. The analysis may involve
system at the Brookhaven National Laboratory in 1957.
preparing slices of the organ and placing the slices on film
Technetium-99m produced via this generator system has
or on phosphorimaging devices so that autoradioradiographic
become the most widely used radionuclide in nuclear medicine
images can be prepared. High resolution images are possible
today accounting for as much as 80% of all diagnostic
due to the short range of the beta rays from the decay of 3 H and
procedures (see table 3 for a list of radiopharmaceuticals). 14
C. Phosphorimagers use a film embedded with light sensitive
The modern era of nuclear medicine has become known
crystal that absorbs the energy of decay of the radioactive
as molecular medicine, as the field translates advances in
substance to form an excited electronic state in the crystals of
molecular biology and biochemistry into the treatment of
the film and the image is read by excitation with a laser digitally
human disease and the diagnosis of pathology and anatomical
stored on a computer. With traditional autoradiography, an
abnormalities. The advent of clinical PET for cancer diagnosis
x-ray film is exposed to the radioactive substance and the film
makes use of sophisticated tracers to unravel cancer biology.
is developed to provide the image. The advantage of the
phosphorimager is that the film can be reused by exposing
4.2. Radioimmunoassay the film to white light to return the crystals to the unexcited
state.
Based on the radioisotope techniques developed in the early
Small animal imaging (SPECT and PET) is an attempt
1950s S Berson and R Yalow published in 1959 the first use
to duplicate this technique, however performed in vivo as
of radioimmunoassay (RIA) to measure the concentration of
discussed below.
insulin in an unextracted human plasma. The RIA principle is
simple and is illustrated by the schematic in figure 6.
The concentration of an unknown amount of unlabeled 4.4. Imaging
antigen can be determined by comparing its inhibitory effect Nuclear medicine imaging differs from other radiological
on the binding of radioactively labeled antigen to a specific imaging techniques in that the radiotracers used in nuclear
antibody with the inhibitory effect of known standards (Yalow medicine relate to the function of an organ system or metabolic
1978). The use of radioactive tracers makes the method pathway and thus the tracing of these agents reveals the
sufficiently sensitive for detecting very small quantities. For integrity of these systems or pathways. This is the basis for
example, in some species, concentrations of less than 1 the unique information that a nuclear medicine scan provides.
picomolar can be determined. The technique involves the
separation of the labeled antigen of interest into bound and Planar imaging. By far the most common imaging device in
unbound fractions after interaction with an antibody in the nuclear medicine is the planar camera or the Anger camera.
presence of an unknown amount of unlabeled antigen. The The basic components of the camera include a thin crystal of
ratios of the bound to free fractions of the labeled antigen are NaI scintillator coupled to a cluster of photomultiplier tubes
compared with the binding of known standards. (PMTs), an X, Y positioning circuit and a readout device
The method of measurement requires only that the antigen that may be an oscilloscope or photographic film. The NaI
in test samples and the antigen in standard samples have scintillator design minimizes multiple interactions with the
identical immunologic behavior. Therefore, it is not necessary incident γ -rays so that the position of interaction can be

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Table 3. Technetium-based radiopharmaceuticals.

Generic name Product name Use Manufacturer
99m
Technetium generator Ultra-TechneKow FM Supply of Tc Mallinckrodt
Technetium generator Supply of 99m Tc Medi-Physics
TechneLite Supply of 99m Tc DuPont-Merck
Aggregated albumin Macrotec Lung imaging Squibb
TechneScan MAA Lung imaging Mallinckrodt
Pulmolite Lung imaging DuPont-Merck
Aggregated albumin Lung imaging CIS-US
MPI MAA Lung imaging Merck Sharp & Dohme
Albumin colloid Microlite Imaging of RE system Dupont-Merck
Serum albumin HSA Kit Blood pool imaging Medi-Physics
Disofenin Hepatolite Hepatobiliary imaging Dupont-Merck
Exametazime Ceretec Cerebral perfusion Amersham
Lidofenin TechneScan HIDA Hepatobiliary imaging Merck Sharp & Dohme
Mebrofenin Choletec Hepatobiliary imaging Squibb
Medronate Osteolite Bone imaging DuPont-Merck
AN-MDP Bone imaging CIS-US
TecheScan MDP Bone imaging Merck Sharp & Dohme
MDP-Squibb Bone imaging Squibb
Medronate Bone imaging Medi-Physics
TechneScan MDP Bone imaging CIS-US
Mertiatide TechneScan MAG3 Renal imaging Mallinckrodt
Oxidronate OsteoSan HDP Bone imaging Mallinckrodt
Penetate sodium DTPA Kidney and brain imaging Medi-Physics
AN-DTPA Kidney and brain imaging CIS-US
Techneplex Kidney and brain imaging CIS-US
Pyro- and tri- metaphosphates TechneScan PYP Bone imaging Mallinckrodt
Phosphotec Bone imaging Squibb
Pyrolite Bone imaging DuPont-Merck
AN-Pyrotec Bone imaging CIS-US
Red blood cell kit Ultratag RBC Bloodpool imaging Mallinckrodt
RB-SCAN Blood pool imaging Cadema
Sestamibi Cardiolite Myocardial imaging DuPont-Merck
Gluceptate Glucoscan Kidney and brain imaging DuPont-Merck
TechneScan Gluceptate Kidney and brain imaging Merck Sharp & Dohme
Succimer DMSA Renal studies Medi-Physics
Sulfur colloid Sulfur Colloid Gastrointestinal and organ studies Medi-Physics
Tesuloid Gastrointestinal and organ studies Squibb
AN-Sulfur Colloid Gastrointestinal and organ studies CIS-US
Teboroxime CardioTec Myocardial imaging Squibb
Source: R Brown, Mallinckrodt, Inc., personal communication, April 6, 1994.

Note: The trade names and the names of the producers may have changed in the intervening years. From Adelstein and
Manning (1995).

Labeled antigen Specific antibody Labeled antigen-antibody complex

Ag* + Ab ↔ Ag*-Ab

Ag Unlabeled antigen in known

standard solutions or unknown samples
↔

Ag-Ab Unlabeled antigen antibody complex

Figure 6. Schematic representation of the reactions used in RIA.

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

determined with great accuracy. Typical scintillation cameras γ

have detectors 25–45 cm in diameter and 0.64–1.27 cm in e-
thickness. e+
The X, Y positioning circuit relies on the light output γ
from the many (19–91) PMTs mounted on the back of the
scintillator. The PMT located nearest to the γ -ray interaction
will receive the maximum amount of light, and the other PMTs
will receive light in proportion to the solid angle subtended by
the tube at the point of interaction. The positioning circuit
11
sums the output of the PMTs and produces X and Y pulses B
proportional to X and Y coordinates of the γ -ray interaction.
In between the radioactive source and the detector is a
collimator constructed of dense metal such as lead or tungsten. 11
The collimator has one or more holes drilled through it to allow C
the passage of γ -rays. Since γ -rays cannot be bent or focused Figure 7. Illustration of positron decay. One of the protons (red) in
the collimator’s function is to absorb those γ -rays that do not the unstable nucleus is converted into a neutron (blue) with the
pass through the openings. emission of a positive electron (positron) which travels a short
In its simplest form the collimator has a single pin hole and distance until it is annihilated with a neighboring atomic electron
resulting in their annihilation giving 2 photons (γ -rays), each with
acts like a camera lens. Other collimators are constructed with
an energy of 511 keV. The photons will travel at nearly 180◦ from
the holes converging, diverging or parallel to the imaginary line each other to conserve momentum.
connecting the object to be imaged and the camera face. The
converging collimator has the effect of magnifying the imaged from 201 Tl having a scatter fraction of as much as 40–50%
object while the diverging collimator magnifies the object. The depending on the depth of the source. It is for these reasons
parallel collimator is used for high resolution. Regardless of that attenuation and scatter exert significant and difficult non-
which collimator is used they all absorb a large fraction of the linear effects that are difficult to correct.
photons emitted by the radiotracer in the patient. Whereas scintillation camera images show the distribution
of the radiopharmaceutical in defined regions in planar view,
Single photon emission computed tomography. As with
they suffer from the superimposition of organs and background
PET, single photon emission computed tomography, SPECT,
contributions to the areas of interest. It is because of these
acquires views of the emitted photons from many different
shortcomings in planar imaging that SPECT has a major role
angles and re-projects these views to reconstruct an image of
to play in diagnostic imaging regardless of whether SPECT can
the three-dimensional distribution of radioactivity in the object achieve the difficult task of providing quantitative information.
or patient. In SPECT, the radiopharmaceuticals used contain The ability to view the distribution in three dimensions greatly
radionuclides such as 99m Tc that emit single photons (ones that affects the interpretation of the images.
are not in timed coincidence with one another). Directional
information is achieved by collimating the photons incident Positron emission tomography. PET imaging makes use of
on the detector of the Anger camera. The collimator thus the self-collimating nature of positron decay (see figure 7), as
reduces the sensitivity of the camera because all of the photons two nearly collinear photons are utilized to define the location
not parallel to the holes in the collimator are prevented from of an annihilation event. PET cameras are typically made of a
reaching the detector surface. ring of detectors that are in timed coincidence (resolving time
Since the reconstructed image contains three-dimensional of a few nanoseconds), allowing a line of response to define
information on the distribution of radioactivity, SPECT also the cord along which the positron was annihilated (the location
has the potential for quantification. The factors effecting this of the emission is not known because of the short distance the
capability are similar to those in PET, e.g. system sensitivity, positron travels before annihilation). By mathematically back-
dead-time, spatial resolution, sampling interval, reconstruction projecting the lines of response, a density map can be generated
filters and the size of the object being imaged. Also, as in PET, that reflects the distribution of the positron emitter.
the photons emerging from the subject are attenuated by the There are several physical limitations inherent to PET
amount of matter between their origin and the detector, and, technology. Firstly, as the emitted positron has kinetic
of course, they have a definite probability of being scattered energy, varying from a few hundred kiloelectronvolts to several
along their path. megaelectronvolts depending upon which radionuclide, it will
Because of the inherently lower energies (100–150 keV) thus travel a few millimeters to centimeters before annihilating
of the photons emitted by radionuclides used in SPECT, the with an atomic electron. As such, the site of annihilation
effect of attenuation can be quite dramatic with reductions is not the site of emission, thus resulting in a limitation
as great as a factor of 5 or more. Thus, with single photon when defining the origin of the decay. Another limitation
emitters, it is difficult to determine whether data reflect a weak is the fact that the positron–electron pair is not at rest when
source near the surface or a stronger source located at some the annihilation occurs, thus by conservation of momentum,
greater depth. In addition, the amount of scatter is strongly the two photons are not exactly collinear. Although the lack
dependent on the energy of the photons, with the photons of co-linearity becomes increasingly important with greater

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Figure 8. The three panels show a combined FDG PET/CT image in transaxial, saggital and coronal views, from left to right. The colored
hot metal image is the PET image and the gray image is from the CT camera. The combined image enables physicians to determine the
precious location of abnormal function (high uptake in the mass visible on the chest wall in the CT image in this case). Photo courtesy of
British Columbia Cancer Agency.

detector separation, this effect is ignored, for the most part, in detector system must be normalized to account for the non-
existing tomographs because the detector ring diameter is less uniform response of the detector system. This is achieved
than a meter at which distance the deviation from 180◦ is a by placing a cylindrical flood phantom of known tracer
fraction of a millimeter. concentration in the field of view and measuring the responses
One of the major strengths that PET has over SPECT is of all detector pairs.
the ability to measure, directly, the attenuation effect of the Other corrections are needed to account for scattered
object being viewed. This is the result of requiring that both photons, which for modern systems can be anywhere from
photons are detected. Thus, if one photon of the pair is not 30% to 50% of the events. The amount of scatter can be
observed then there is no line of response. Along the path to the reduced by selecting a narrow energy window of acceptance
detectors, one or both photons (511 keV each, the rest mass of so as to eliminate large angle scatter (large angle scatter results
the electron) can undergo absorption by the photoelectric effect in lower energy of the scattered photon). This will however
or Compton scattering when interacting with surrounding reduce the efficiency. The remaining scatter profile is removed
material. Thus, in order to be detected as an event, both photons by analytical techniques, a discussion of which is beyond this
must be detected in temporal coincidence. By using an external review.
source of positron emitter, the attenuating (absorbing) extent Finally, there are random coincidences that must be
of the object to be measured can be determined. However subtracted. Because of the finite timing window for defining a
that advantage has been eliminated now that all commercial coincidence, there is the possibility of unrelated events arriving
PET (and many SPECT) cameras are built with a CT scanner within the timing window. The number of random events is
(x-ray tomography) so that a merged image of structure and related to the size of the timing window and the count rate in
function can be obtained. In addition, as the CT image any one detector. Random events can be reduced by using fast
is a measure of electron density, it is used to calculate the detectors and electronics which enable a short timing window
necessary coefficients for attenuation correction. However, to be employed. Randoms are usually estimated by monitoring
the calculated attenuation coefficients are difficult to perform the single event rate and subtracting globally from the image.
in the thorax. Nevertheless, the use of the CT image is standard Once all of these corrections are applied the resulting
for attenuation corrections now although its primary function image can be displayed as what is called a parametric image.
is to provide a detailed view of the section of the body under In its simplest form this will be disintegrations per second
investigation. Figure 8 illustrates the power of this approach. for the volume element of the image. If a mathematical
Once the attenuation of the object is measured and the model is employed that describes the time course of the
radiotracer is injected the temporal and spatial distribution of tracer the images can be presented as metric describing a
the tracer may be determined. However, to make a quantitative biological function such as glucose metabolism when using
18
estimate of the distribution there are other corrections required. F-fluorodeoxyglucose (FDG) or the binding potential in
First of all, for true quantitative extraction of information the measuring receptor concentrations. The binding potential is

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

related to the ratio of the receptor concentration (Bmax ) and the Table 4. Radionuclides used in imaging for SPECT and PET
affinity of the tracer for the receptor (KD ). studies.
The heart of the PET camera is the detection system. SPECT PET
The vast majority of modern PET scanners make use of 99 m 11
Tc C
segmented inorganic scintillation crystals coupled to multiple 201
Tl 18
F
PMTs. The ideal crystal will have a high stopping power for the 67
Ga 64
Cu
511 keV annihilation photons (high photoelectric absorption), 123
I 124
I
a high light output with wavelength matched to the PMT, a
fast decay time for the light and be physically robust. For
nearly two decades the detector material of choice was bismuth resulting from PET is of great importance. Nevertheless, the
orthogermanate (BGO). More recently lutetium orthosilicate true power of PET is its ability to track the distribution of a
(LSO) has been introduced. Due to its higher light output, tracer over time and extract detailed kinetic data as in a physical
the segmentation of the crystals could be finer, thus reducing chemistry experiment where rate constants are determined. So
the crystal element size from approximately (4 mm × 4 mm) the conflict between using the technology for clinical diagnosis
to (2 mm × 2 mm). There are proposals to reduce the crystal versus using PET as an in vivo biochemistry tool will not be
elements to below 1 mm2 . In order to accomplish such a task, easily resolved, nor should it be.
the packing fraction of the crystals must be improved; in other With the advances in the technology enabling increasingly
words, the empty space between crystal elements must remain better resolution, it has become possible to build PET scanners
a small fraction of the total area. capable of imaging small animals. The pharmaceutical
The typical crystal is segmented into an 8×8 grid (or more) industry has recognized the power of using such small animal
coupled to four PMTs. There is an algorithm to identify the PET scanners as a screening tool for their pre-clinical research.
location of the event by comparing the light sharing amongst PET can be used as a surrogate to monitor changes in
the PMTs. While this scheme reduces the cost of the scanner metabolism or receptor occupation or by labeling the drug
there is a loss in resolution due to the approximate nature of directly and determining the distribution and time course of
the light sharing approach. There are prototype scanners using the compound, in vivo. One of the strengths of PET in this
avalanche photodiodes coupled to individual crystal elements regard is that animals can be used many times so that they can
making the finer pixel identification better. Thus far, such serve as their own controls and changes due to interventions
systems have been built only for small animal scanners. monitored. Such an approach reduces the number of animals
Functional imaging using PET started as a research tool required and increases the statistical power of the study. See
in neuroscience in the late 1970s and still remains a major below for more details on small animal scanning.
research tool for current-day neurosciences. However, its Pharmaceutical companies also recognize that human
major impact recently has been in the diagnosis of cancer. PET scanning can be used as surrogates for monitoring the
While simple tracer molecules such as water, carbon monoxide therapeutic efficacy of drugs in phase II and III drug trials.
and carbon dioxide had been used for many years the first By performing baseline scans and scans at intervals following
complex molecule to be used extensively was the glucose intervention, the PET data can often reveal biochemical
analog, 18 F-fluorodeoxyglucose (FDG), developed at the changes much sooner than the clinical signs—thus shortening
Brookhaven National Laboratory (BNL) in collaboration with the assessment time. Most often surrogate markers are used to
researchers at the National Institutes of Health in the US and monitor a particular functional change.
the University of Pennsylvania around 1975. Since the human As the physical limitations of detection are approached,
brain uses glucose as its primary energy source, the availability the remaining avenue is to increase the signal to noise by
of the tracer led to ground-breaking work for studying the utilizing tracers that are uniquely suited to imaging the function
human brain in health and disease. This effort was driven by in question and otherwise clear rapidly from surrounding
the successful use of 14 C labeled deoxyglucose at the NIH by tissue. To this end, the development of more specific tracers is
Louis Sokolov in the 1960s. Since 14 C is not detectable from believed to be the most critical component for PET.
outside of the body, the effort went into developing a labeled
analog that could be shipped from a cyclotron facility (BNL in Radionuclides in imaging. While there is a wide range of
this case) and the PET camera (the University of Pennsylvania). radionuclides that are used in imaging, a relatively small
Thus F-18 with its nearly 2 h half-life became the radionuclide number make up the vast majority of all studies in SPECT
of choice. and PET imaging. Table 4 lists the most widely used
Today, many more tracers are used to investigate the radionuclides for imaging along with a couple of potentially
various neuronal systems probing both the presynaptic and useful radionuclides.
the postsynaptic pathways. Several hundred tracers have been For the SPECT agents, 99m Tc is the most widely used
prepared and tested for the utility in investigating various accounting for approximately 80% of all studies in nuclear
enzymatic and receptor systems while only a handful are medicine. This is primarily due to its availability through the
99
routinely used. There are tracers specifically designed to Mo/99m Tc generator as discussed earlier. Tl-201 is widely
monitor cell proliferation, the hypoxic nature of cells and cell used in cardiac studies as thallous chloride. The Tl+ ion is an
apoptosis. analog of K+ which is used in muscle function.
Because diagnostic imaging is driven by a digital approach Ga-67 as a citrate is used to detect inflammation and I-123
(present/absent, yes/no) the desire to have uncluttered images is used in a variety of radiopharmaceuticals to image brain,

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Table 5. Nuclear reactions used to produce imaging radionuclides have high specific activity 123 I available for labeling. However,
from accelerators. the production costs are still relatively high in comparison with
Energy other radionuclides, which will make its use limited for the
Radionuclide t1/2 Reaction (MeV) foreseeable future. While 123 I can be produced for local use
99m
Tc 6.0 h 100
Mo (p,2n) 30 via the 123 Te(p,n) or 124 Te(p,2n) reactions, the co-production
123
I 13.1 h 124
Xe(p,2n)123 Cs 27 of 124,125 I limits the product’s shelf-life.
124
Xe(p,pn)123 Xe Although 99m Tc can be produced on an accelerator its
124
Xe(p,2pn)123 I production in a reactor by extraction of its parent, 99 Mo, from
123
Te(p,n)123 I 15 235
124
Te(p,2n)123 I 25
U fission products is much cheaper and more efficient.
201 203 Thalium-201 has been extensively used for more than 30
Tl 73.1 h Tl(p,3n)201 Pb→201 Tl 29
11 14
years to assess cardiac blood flow as a K+ analog. Over this
C 20.3 m N(p,α) 11–19
11 period there have been numerous reports of its demise, yet the
B(p,n) 10
18 18
growth in demand for this isotope is still upward.
F 110 m O(p,n) 15
20 The remaining isotopes listed are used in PET imaging.
Ne(d,α) 14
nat
Ne(p,X) 40 Carbon-11 is extremely attractive because, in principle, one
64
Cu 12.7 h 64
Ni(p,n) 15 can replace an existing carbon atom in the molecule of interest
68
Zn(p,an) 30 with the radioactive isotope. However, because of the short
nat
Zn(d,axn) 19 half-life, its availability will be limited to those sites that
nat
Zn(d,2pxn) 19 either possess an accelerator or are close to an accelerator.
124
I 4.14 d 124
Te(p,n) 13 The demand for 18 F exceeds its availability. To overcome
125
Te(p,2n) 25 this shortage, a number of central distribution centers have
been placed in large metropolitan areas in North America,
Europe and Asia. Although several nuclear reactions are
heart and kidney function. The variety of compounds available available, the (p,n) reaction is the route of choice for producing
is based on the ability to chemically insert iodine into complex large quantities of 18 F. If the availability of 18 F continues to
molecules. grow, 18 F-labeled compounds may begin to compete with other
Of the PET radionuclides F-18 is by far the most widely SPECT agents such as 123 I.
used, principally due to its use in FDG. The fluorine atom is The other two isotopes, 64 Cu and 124 I, are candidates for
about the same physical size as the hydrogen atom in most both PET imaging and possible use in therapy (see below).
molecules; thus F-18 is used as a hydrogen substitute. A large The interest in these two is primarily related to the relatively
number of molecules have been labeled with F-18. C-11 is long half-lives. Such properties would enable studies to be
also widely used because of the obvious isotopic substitution performed where the in vivo kinetics are slow and exceed
for C-12. The principal disadvantage of C-11 is its short the ability to image with 18 F. The disadvantages include low
half-life (20 min) which limits its availability to sites with an production rate (124 I) and the need for expensive enriched
accelerator. Cu-64 has a half-life of just over 12 h and is thus target material (64 Ni, 124 Te (<1% and <5% natural abundance,
of interest to probe systems which have a long biological half- respectively)). Results from Washington University in St Louis
life. I-124 has the advantage of being easily inserted in a wide have shown that even with the high-energy β + -particles
range of molecules but its 4 d half-life limits its utility due to associated with 124 I decay and other photons in coincidence
high radiation exposure. with the β + -decay, they can still be imaged at high resolution
Table 5 provides various low energy production routes (64 Cu) (McCarthy et al 1997, Lewis et al 2003).
along with the half-life of the radionuclides. Technetium- PET imaging has been in use for several decades for
99m is included since this isotope alone accounts for nearly human brain and whole body imaging, first only as a research
80% of all nuclear medicine imaging studies. There have tool, now gaining acceptance as a diagnostic imaging modality
been a number of proposals suggesting that 99m Tc could in selected applications such as oncology and, very recently,
be produced at an accelerator. However, the economics of as an aid in the diagnosis of Alzheimer’s disease. All of
accelerator production cannot compare with the extremely low these advances are made possible through the improvement in
costs of producing it at a reactor. While there is concern about resolution and sensitivity of the scanners but more importantly
the ability to build new reactors and the availability of this by the development of more specific tracers.
important isotope may be jeopardized, the recent construction
of reactors in Canada dedicated to 99 Mo production and the Small animal scanning (Sossi and Ruth 2005). Compared
upgrade of other facilities around the world will remove this with human PET scanning, small animal PET presents new
concern for the present. challenges, both of instrumentation and biological nature.
Iodine-123 has been of interest for nearly three decades However, it also offers the possibility of performing in vivo
because of its unique chemistry that makes it possible to attach testing of new pharmaceuticals while at the same time allowing
this isotope to a wide variety of molecules and the γ -ray energy for the possibility of direct correlation between in vivo and
(159 keV) that is matched well to SPECT cameras. The ability in vitro measurements thus indirectly providing a deeper
to produce this isotope in high purity from enriched 124 Xe understanding of the human PET measurements. For the most
targets made it possible to ship 123 I over long distances and still part the use of small animal scanning has been dominated by

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

research in oncology because of the existing animal models metabolism via the use of the labeled drug or to measure
of tumor biology and the relative ease of placement of the the efficacy of action through the use of other PET tracers
tumor in a location with low background. With the increased as surrogate markers of the drug role in altering function
availability of animal models of disease especially in cancer (Langstrom et al 1995). While labeling the drug directly
biology where a wide variety of tumor models are not only may present some challenges, the labeled drug is seen as an
being developed but mice are being genetically modified to important tool for those compounds directed at brain function
spontaneously produce tumors, small animal imaging is being since an estimate of the degree that (and even whether) a drug
used to test new therapies as well as developing more specific penetrates the blood–brain-barrier is required before further
diagnostic tests. In addition, small animal imaging has been drug assessment. In addition, the concentration at which a
steadily expanding into the areas of brain and neuroreceptor drug has an effective action is often associated with plasma
imaging with a variety of different tracers. concentrations when in fact this relationship may not really be
The challenges associated with small animal scanning can measuring the effect of the drug in the brain. The true effect
be divided into the physical and biological issues as discussed can be measured via PET, either with labeled drug or with
below. surrogate molecules.
a. Instrumentation related challenges. The biggest In drug design a particular neuronal system is to be
instrumentation challenge that needed to be overcome to altered through blocking enzymes, intercepting transmitters
successfully apply PET imaging to small animals was to or occupying receptors. Using tracers that are sensitive to
increase spatial resolution, while still maintaining high these changes can provide the needed information in a time
detection sensitivity. For example, the spatial resolution of frame measured in minutes to hours as opposed to waiting for
traditional human PET scanners ranges typically from (4 mm)3 a pharmacological effect which may take days if not weeks.
to (9 mm)3 , while the size of a rat or mouse organ is orders of As mentioned in the introduction, the ability to assess the
magnitude smaller compared with the size of the corresponding effects of an intervention longitudinally, on the same animals,
human organ. significantly reduces the variability of the final results and
b. Biology related challenges. The small size of the animals makes better and more efficient use of the animals themselves.
limits the amount of the tracer that can be administered in d. Comparison with post-mortem measures. A unique
a scanning session: PET is based on the tracer principle, advantage of small animal imaging is the ability to use the
that is, the administered radiotracer must not influence the same animal as its own control and to perform longitudinal
process under investigation. In receptor imaging this is studies. In more traditional animal studies multiple animals
satisfied when the tracer does not occupy more than 1% of were required at various time points so that the animals could
the available receptors (Hume et al 1998). This requires be sacrificed and studied to determine the time course of the
tracers to be produced at very high specific activities (generally function under investigation. With small animal scanning
>37 GBq µmol−1 ) and limits the amount of radioactivity that the time course can be measured directly, even over days
can be injected, thus rendering detection sensitivity even more if necessary. The challenge with longitudinal studies is to
important. reposition the animal so that the regional data are correlated.
The second complication due to the small physical size e. Radiotracer and chemistry development. Future advances in
is the fact that the size of the animal’s blood pool is very functional imaging using nuclear techniques, especially PET,
small. This has direct implications on the applicability of are dependent on tracer development. The PET scanner only
biological models that are applied to the PET data to extract measures radioactive decays and cannot by itself identify a
biologically relevant parameters such as binding potentials and biological process of interest. To understand the time course of
process rate constants. Many of these models in fact rely on the tracer, the careful design and development of the radiotracer
an input function derived from the radiotracer concentration in to make it as specific as possible for the relevant biological sites
plasma, measured by the extraction of several blood samples. and processes, while minimizing nonspecific binding to other
Such blood sampling is often not possible with these small tissue types, is required (Okarvi 2001, Kawamura 2003). As
animals; therefore, analysis methods that utilize tissue input the imaging instrumentation becomes more powerful, there
functions must be used. Such methods require a region where is an increasing demand for new tracers as more sites and
there is no specific binding of the tracer and appropriate regions processes become potentially observable in vivo. In addition to
must be accurately identified for each tracer. Conversely, some undergoing in vitro validation however, the new tracers must
research groups are looking into the possibility of measuring undergo a rigorous validation of their in vivo behavior and,
the plasma input function from the image of an animal organ, where necessary, new imaging protocols and analysis methods
such as the heart (van der Weerdt et al 2001). However, must be developed. Presently there are a number of small
this is in practice only feasible when the radiotracer does not molecules that have been used in human PET scanning for
undergo significant metabolism: the PET scanner only detects years as well as in small animal autoradiographic studies using
radioactivity and is not able to separate the chemical form of the 3 H- and 14 C-labeled versions. In order to have sufficient
the radioactively labeled substance. signal for the PET scanner the tracers have to be of sufficiently
c. Testing of new drugs and their efficacy. Small animal PET high specific activity (radioactivity units per mass) to provide
imaging is an ideal tool in the process of new drug development a high-count rate while not violating the tracer principle. The
and evaluation of treatment efficacy (Campbell 1995). PET specific activity required to maintain this principle is on the
imaging can be used to either follow a drug distribution and order of 37 GBq µmol−1 (Hume et al 1998). Thus when

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Figure 9. Placement of the PET insert inside a 7-T MRI scanner: photograph (a) and drawing (b) show magnified views of insert and the RF
coil in place inside the MR scanner and drawing (c) shows axial placement (Catana et al 2006).

Figure 10. Black and white MRI images and merged FDG PET images with the MRI scans (Judenhofer et al 2007).

injecting a few MBq of a tracer with such specific activities 4.5. Radionuclides for therapy
the resulting mass of the injected tracer would be on the order
The idea of a radionuclide used in therapy is based on the
of tens of picomoles. In addition to the need for high specific
desire to link a radionuclide which has a high linear energy
activity there is a need for high radioactivity concentration
transfer associated with its decay products such as Auger
(radioactivity units per volume of solution). This requirement
electrons, β-particles or α-particles to a biologically active
stems from the fact that the volume that can be injected into
molecule that can be directed to a tumor site. Since the
rodents is on the order of 0.5 mL, maximum because of the
β − -emitting radionuclides are neutron rich they have, in
small blood volume of the animal (typically 20 mL for rats and
general, been produced in reactors although a few are best
2 mL for mice). While there are no requirements to produce
produced via charged particle reactions. Astatine-211 is one
the tracers under regulatory conditions, it is obvious that the such radionuclide [209 Bi(α,2n)211 At]. Table 6 provides a list
tracer must be of the highest purity in order to preserve the of radionuclides considered suitable for therapy along with
integrity of the study (Sossi and Ruth 2005). their physical characteristics while table 7 contains the nuclear
Just as with human scanning, small animal PET has been reactions that can be used for selected radiotoxic nuclides.
combined with CT scanners. However, there is a complication The attractive feature of 77 Br is its chemical versatility
associated with the high radiation dose from the CT adversely in addition to its half-life. Production rates are relatively low
affecting the animal under investigation. Thus the power of and purity may be an issue since 76 Br is often co-produced.
the x-ray beam must be monitored, especially if the animals The demand for 103 Pd, which is used in treating prostate
are to have serial scans. Nevertheless the images are exquisite. cancer, is continuing to grow. A large number of low energy
To overcome this difficulty and to provide even more (19 MeV) cyclotrons are dedicated solely to the production of
information in a single setting investigators are developing this isotope.
combined PET-MRI devices. Unlike the PET/CT systems Yttrium-90 is an attractive radionuclide for therapy
which are two scanners built back-to-back, the PET/MRI because it is a pure β − emitter and is the product of 90 Sr decay.
systems are integral as shown in figure 9. Strontium-90 has a long half-life (28.8 years) and is readily
The development of this technology is moving forward available as a fission product from nuclear reactors. Because
rapidly and is being applied to human studies as well as Y-90 does not have an imageable γ -ray, another isotope of
illustrated in figure 10 which shows early images from an F-18 yttrium or one of similar chemical properties must be used. In
FDG scan. most instances 111 In has been used as the surrogate.

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Table 6. Radionuclides that have been proposed for use as possible

Receptor
radiotoxic isotopes for treating cancer.
Emission
Isotope Half-life (h) (for therapy)
Bromine-77 58 Auger electrons
Iodine-131 (131 I) 192 β
Yttrium-90 (90 Y) 64 β
Lutetium-177 (177 Lu) 161 β
Copper-67 (67 Cu) 62 β Antibody
Rhenium-186 (186 Re) 90.5 β Cancer Cell
Rhenium-188 (188 Re) 16.9 β
Bismuth-212 (212 Bi) 1 α Figure 11. Schematic illustrating the antibody labeled with a
Bismuth-213 (213 Bi) 0.77 α radiotoxic isotope and how the antibody targets specific receptors on
Astatine-211 (211 At) 7.2 α the cancer cell. As the radioisotope decays there is a high
Actinium-225 (225 Ac) 240 α probability that some of the beta particles will break the DNA
strands in the cell nucleus initiating cell death (drawing courtesy of
S Lapi, Simon Fraser University, Burnaby, Canada).
Table 7. Production routes for selected therapy radionuclides.
Decay Energy α-particle associated with it. Because of its short half-life
Radionuclide t1/2 mode Reaction (MeV)
multiple production sites would be required. Thus the interest
77
Br 2.4 d Auger 75
As(a,2n) 27 in producing its parent radionuclide (211 Rn, t1/2 = 14.6 h) has
77
electrons Se(p,n) 13 been suggested as a way of producing and shipping 211 At to
78
Se(p,2n) 24
79,81
remote sites.
Br(p,xn)77 Kr 45
nat
Mo(p,spall.) >200 In spite of its long half-life there is growing interest in the
90 − 90 use of Ac-225. The concern with the long half-life is related
Y 2.7 d β Sr decay Sr-fission
product to the redistribution that may occur during its residence in the
103
Pd 17.5 d Auger 103
Rh(p,n) 19 body following a therapeutic injection.
electrons nat Ag(p,xn) >70
186 185
Re 90.6 h β¯ Re(n,γ ) Thermal
186
W(p,n) 18 4.5.1. Targeted radionuclide therapy. In order for these
186 radionuclides to be effective at cancer cell killing, they must
W(d,2n) 20
197
Au(p,spall.) >200 either be located at or near the cancer cells (high LET particles)
nat
Au(p,spall.) >200 or near the DNA in the nucleus (Auger emitters). Major
nat
Ir(p,spall.) >200
211 209
research efforts have gone into finding the magic bullet, that
At 7.2 h α Bi(α,2n) 28
209
Bi(7Li,5n)211 Rn 60
is achieving site directed delivery of the radionuclide. Most
232
Th(p,spall.)211 Rn >200 efforts have centered on the use of monoclonal antibodies that
are substrates for specific receptors associated with specific
cancer cells. Receptors are proteins usually on the cell surface
Rhenium-186 is attractive for a number of reasons. It has that are used by the cell that act like signal transducers, receive
the desirable physical characteristics of being a β − -emitter chemical signals from other cells, thus acting as receptors of
with a useful half-life (90 h) and a γ -ray (137 keV) that chemical information. Each of these receptors has unique
can be imaged with standard SPECT cameras. This ability chemical and physical (spatial) properties so that only certain
to be imaged provides a strong case for its use since molecules can be bound or received by the receptor. A
radionuclide therapy agents are often pure β¯ emitters and close analogy is a lock and key concept. Recently two
require a surrogate radionuclide for distribution information.
commercial products have appeared on the market that are
In addition, rhenium is in the same chemical family as
based on this concept, antibodies labeled with radionuclides
is technetium; thus much of the chemistry developed for
(Zevalin® , labeled with 90 Y (t1/2 = 2.7 d) and Bexxar® labeled
technetium can be applied to rhenium. The production from
with 131 I(t1/2 = 8 d)) (Health Canada (Bexxar) 2005; Health
the neutron capture reaction leads to a low specific activity
product which limits its shelf-life and may also limit its utility Canada (Zevalin) 2005).
as a radiotoxic species when attached to a chemical vehicle Figure 11 illustrates the steps in targeting cancer cells
such as an antibody. Production rates from all of the reactions with labeled antibodies. The radionuclide must be attached
from charged particles for this radionuclide listed in table 7 to the antibody in such a way as not to impact the recognition
are very low. Thus the only practical route to this potentially properties of the antibody for the specific receptor on the cancer
important radionuclide is via neutron capture in a reactor. cell. With β-particle radiation the damage does not have to
And finally, α-emitting isotopes have been of interest occur on the cell on which the antibody is attached. With the
for use in therapy because of the high LET associated with range of particles representing a few cell diameters there is the
the α-decay. Astatine is of interest because it possesses possibility of damage to neighboring cells. This concept is
many properties of halogens and each decay of 211 At has an referred to as the crossfire effect.

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

5. Radiopharmaceuticals neurotransmission, receptor density and occupancy have all

been measured via appropriately designed radiotracers. It
The term radiopharmaceutical is applied to a biologically should be pointed out that the development of radiotracers
active compound that either has a radionuclide attached or for PET fundamentally violates rule number 2 for the ideal
in the elemental form behaving as a radiotracer that can be tracer because PET radionuclides, by nature, emit β + particles.
safely administered to humans. The safety of these molecules However, the resulting coincident γ -rays from β + annihilation
is determined by their radionuclidic and radiochemical purity form the basis for the technique.
and that they are sterile and free from micro-organisms that In addition to consideration of the above principles, the
can cause fevers (pyrogens). radiochemist must plan how to insert the radionuclide into
Radiopharmaceuticals differ in one major aspect from the molecule at a point in the synthetic process where there
regular pharmaceuticals in that they are given in such small is minimal handling, yet late enough in the synthesis to
concentrations that they do not elicit any pharmacological minimize loss due to chemical yield and radioactive decay. For
response. Because of this there have been a number of attempts these reasons the preparation of radiopharmaceuticals requires
to change the name used to describe these substances to, planning and techniques not encountered by traditional
for example, radiotracers. Present-day radiopharmaceuticals synthetic chemistry.
are used for diagnostic purposes in about 95% of the cases The development and use of PET tracers can be viewed
and the remainders are used in therapy. However the use of as covering two major areas: (1) tracers that can be used as
radiopharmaceuticals in therapy is seen as the next major area surrogate markers for biological processes and (2) those tracers
for growth in the use of radionuclides. that are specific for a particular process, whether it is intended
In order for a radiotracer (radiopharmaceutical) to be used to measure enzyme activity or receptor concentration or the
in humans safely it must meet the quality standards that include expression protein synthesis. A major hindrance in tracer
chemical and radiochemical purity and it must be sterile and development is the complex nature of the synthesis process
free from pyrogenic material. itself. While major steps have been made to simplify the
The ideal radiopharmaceutical for imaging should synthetic steps there are still areas in need of improvement
such as miniaturization of the synthesis instrumentation.
(1) be readily available at a low cost, Miniaturization provides the opportunity to use small amounts
(2) be a pure gamma emitter, that is no α and β (such particles of starting materials and radioactivity that would make the
contribute radiation dose to the patient while not providing purification simpler and easier. Simple solid phase columns
any diagnostic information, (see the section on dosimetry); could be used instead of cumbersome high performance liquid
this is, of course, not followed with PET), chromatography. In addition, if the miniaturization can be
(3) have a short effective half-life so that it is eliminated from realized it is conceivable that multiple compounds could
the body as quickly as possible, be prepared in parallel for testing with a single supply of
(4) have a high target to non-target ratio so that the resulting radionuclide. This can be viewed as the radiochemist’s attempt
image has a high contrast, that is the background does not at screening compounds.
blur the image,
(5) possess proper metabolic activity in that it follows or is
trapped in the metabolic process of interest. 6. Environmental/biological applications

Radioisotopes can be used to help understand chemical and

The ability to measure regional biochemical function requires a biological processes in the environment and in plants. There
careful design process with these principles in mind. However, are two reasons for this usefulness. Radioisotopes are
in reality it is not possible to meet all of these criteria. For chemically identical to other isotopes of the same element
example, all decay processes involve the emission of particles and will react in the same way in chemical reactions and for
as in the case of pure γ -emitters which have Auger electrons many elements some radioactive isotopes of the element have
emitted during some fraction of the decays. Thus, it is appropriate half-lives and can be easily detected. In other
necessary to address the following steps (Eckelman and Gibson situations elements or simple molecules can be constructed
1993) in the development of a biochemical probe: to have similar chemical or physical properties of the chemical
systems to be probed. In using surrogate markers their use
(1) develop a radiotracer that binds preferentially to a specific needs to be validated through experimentation.
site;
(2) determine the sensitivity of the radiotracer to a change in
biochemistry; 6.1. Agricultural applications
(3) find a biochemical change as a function of a specific There are many applications of radioisotopes in agriculture.
disease that matches that sensitivity. Radiation has been used to breed new seed varieties with higher
yields, such as the ‘miracle’ rice that has greatly expanded rice
A large number of radiotracers have been synthesized to probe production in Asia. The ionizing radiation from radionuclides
metabolic turnover such as oxygen consumption, glucose increases the number of variations in plants and, with careful
utilization and amino acid synthesis. Enzymatic activity, selection, can produce crops that are more drought and disease

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

resistant, as well as crops with increased yield or shorter at the same time reducing harmful environmental effects of
growing time. This practice has been in place for several excessive nitrogen use.
decades and has helped feed some third-world countries. All of these studies involved using N-13 labeled nitrate
Radioisotopes are ideally suited as tools for the and or ammonia in the lab under controlled conditions.
investigations of fertilizers. Important plant nutrients, such The use of C-11 (t1/2 = 20.3 min) provides the
as calcium, phosphorus, iron, potassium, copper, sodium, opportunity of producing more complex molecules as is seen
sulfur, and zinc, have radioisotopes with appropriate half- in the medical applications discussed earlier.
lives and decay characteristics to be used as tracers. These This example illustrates how the use of radiotracers has the
elements can be incorporated in fertilizers and applied to the potential to impact what is understood about plant physiology
soil to determine the effect on plant utilization of fertilizer and the effect of nutrients in the environment. Details of these
composition or the method of application. Plant uptake of studies and more are provided in the readings listed.
the activated fertilizer can be readily measured and can be
distinguished from the uptake of the same compound already 6.3. Earth and ocean sciences
present in the soil.
See the section below on plant physiology which Radiotracers are used studying the biological production
explores some fundamental mechanisms that affect plant in aquatic environments. For example, Si-32 is used to
estimate the rates of silicon uptake by diatoms. Diatoms, a
interactions with the environment, both natural as well as
group of aquatic algae, are one of the largest contributors to
artificial.
carbon fixation accounting for up to 75% of marine primary
production. They have absolute requirements for silicon,
which is precipitated as amorphous hydrated silica in their
6.2. Plant physiology
cell walls. Hence, diatoms control the cycling of silicon and
Probably the most widely used tracer for studies in tracer contribute significantly to the downward flux of biologically
kinetics in plants is N-13. In spite of its relatively short produced silica, nitrogen and carbon in most oceanic regions.
half-life (<10 min) a wide variety of studies have been Accurate determination of diatom growth is essential for
undertaken to understand the incorporation of nitrogen into understanding global nutrient cycling and biogeochemical
plant systems (Britto 2004). These studies have had a wide modeling.
impact on understanding the adaptive abilities of plant systems Another radiotracer that is being used to further our
associated with changing environmental conditions to monitor understanding of the carbon cycle and the oceans is Cu-67. Iron
the nitrogen content of genetically modified rice in attempts (Fe) is an essential micronutrient for phytoplankton growth
to increase the protein content of rice species as the primary and has been shown to control primary productivity in large
protein food around the world. oceanic regions. However the role of copper in this process
By examining the roots of rice plants and the manner in is poorly understood. With the Cu-67 62 h half-life it has
which cellular pools of carbohydrates and various nitrogen become possible to use this isotope as a tracer in deep ocean
compounds regulate the expression of three ammonium studies without having to store and transport the samples back
transporter genes by measuring the ammonium influx using to the lab.
13
NH+4 , the researchers found that N and C interact at the
cellular level so that the supply of N provided by the root 6.4. Insect control
ammonium transporters matches the availability of carbon
About 10% of the world’s crops are destroyed by insects.
compounds provided by leaf photosynthesis.
These pests can sometimes be controlled by releasing sterile
This research team has investigated the effect of different laboratory-raised insects into the wild. The male insects are
transport systems in the root system by genetically modifying made sterile using ionizing radiation. Female insects that
Arabidopsis (a small flowering plants related to cabbage and mate with sterile male insects do not reproduce, and the
mustard) to express one of the two transporter genes. They population can be quickly curbed as a consequence. The
have demonstrated that one mutant is unable to grow normally technique is considered to be safer and better than conventional
when the nitrate is the sole source of N and that the 13 NO− 3 chemical insecticides since insects can develop resistance
uptake is dramatically reduced. Thus high-affinity nitrate against insecticides, and there can be health concerns about
uptake requires participation of genes encoding both the type chemically treated crops.
of transporter proteins.
A large portion (perhaps >50%) of applied nitrogen
6.5. Water resources
fertilizer is lost from soils. One significant proportion of this
loss is attributed to ammonium blocking nitrate uptake. Using Adequate water is essential for life. However in many parts of
the fungus Aspergillus as a model system this team studied the the world water is scarce and in others it is becoming scarcer.
mechanism of this effect. They found that the effect is rapid Isotope hydrology makes accurate tracing of underground
and due to ammonium per se not to its metabolic product, e.g. water resources possible. These techniques are important
glutamine. They are investigating whether the protein can be analytical tools in the management and conservation of existing
modified so it can be eliminated in transgenic plants to reduce water supplies and in the identification of new, renewable
nitrate losses from soil and improve fertilizer utilization while sources of water. The results permit planning and sustainable

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

Table 8. Common radionuclides and their uses.

Calcium-47 Aid to biomedical researchers studying the cell function and bone formation of mammals.
Carbon-11,14 Used in research to ensure that potential new drugs are metabolized without forming harmful by-products.
Cesium-137 Used to treat cancers; to calibrate the equipment used to measure correct patient dosages of radioactive
pharmaceuticals; to measure and control the liquid flow in oil pipelines; to tell researchers whether oil wells are
plugged by sand and to ensure the right fill level for packages of food, drugs and other products. (The products
in these packages do not become radioactive.)
More recently, Cs-137 has become the radioactive source by which attenuation is measured in PET scanners.
Chromium-51 Used in research in red blood cell survival studies.
Cobalt-57 Used in nuclear medicine to help physicians interpret diagnostic scans of patients’ organs and to diagnose
pernicious anemia.
MicroPET scanners make use of Co-57 as the radioactive source by which attenuation is measured in small
animals.
Copper-64 Used in small animal PET imaging. Considered a potential radiotherapeutic.
Fluorine-18 Primary radionuclide used in PET imaging, generally substituted for hydrogen in biologically active molecules.
Gallium-68 Generator produced PET radionuclide.
Germanium-68 In equilibrium with its positron emitting daughter has been used as an attenuation source for PET scanners as well
as a source for Ga-68.
Iodine-123 Widely used to diagnose thyroid disorders.
Iodine-129 Used to check some radioactivity counters in in vitro diagnostic testing laboratories.
Iodine-131 Used to diagnose and treat thyroid disorders such as Graves’ disease.
Nitrogen-13 In the chemical form of ammonia N-13 is used as a blood flow marker in cardiac studies. Also used in plant
physiology studies (NO− − +
2 , NO3 and NH4 ).
Oxygen-15 Used in brain studies in various chemical forms to monitor blood flow (H2 O), Oxygen metabolism (O2 ), and
blood volume (CO)
Phosphorus-32 Used in molecular biology and genetics research.
Rubidium-82 Used as a potassium analog to measure cardiac blood flow with PET
Selenium-75 Used in protein studies in life science research.
Sodium-24 Used to locate leaks in industrial pipelines and in oil well studies.
Strontium-85 Used to study bone formation and metabolism.
Technetium-99m The most widely used radioactive isotope for diagnostic studies in nuclear medicine. Different chemical forms
are used for brain, bone, liver, spleen and kidney imaging and also for blood flow studies.
Thallium-204 Measures the dust and pollutant levels on filter paper and gages the thickness of plastics, sheet metal, rubber,
textiles and paper.
Tritium (H-3) Used for life science and drug metabolism studies to ensure the safety of potential new drugs; for self-luminous
aircraft and commercial exit signs; for luminous dials, gauges and wristwatches and to produce luminous paint.
Uranium-235 The source of Tc-99m and other important medical radionuclides when the U-235 undergoes fission.
Uranium-238 Used in dental fixtures such as crowns and dentures to provide natural color and brightness and in fuel for nuclear
power plants and naval nuclear propulsion.
Xenon-133 Used in nuclear medicine for lung ventilation and blood flow studies.
Yttrium-90 Radiotherapeutic nuclide used in combination with antibodies to treat cancer.

management of these water resources. Neutron probes imaging, while the big challenge in the next few years
can measure soil moisture very accurately, enabling better will be for the chemists to develop tracers that are more
management of land affected by salinity, particularly with specific and reflective of the functional condition under
respect to irrigation. investigation, while miniaturizing the chemical synthesis and
For surface waters they can give information about related instrumentation.
leakage through dams and irrigation channels, the dynamics Two major areas related to tracer development will include
of lakes and reservoirs, flow rates and river discharge rate the miniaturization of the chemistry for preparing tracers. With
measurements and silt sedimentation rates. Many countries, the advent of microfluidics and lab-on-a-chip technology, the
developed and developing, have used isotope techniques to automated syntheses of tracers on a wafer that can be discarded
investigate their water resources in collaboration with the are not far away. Such developments will speed the availability
IAEA. of tracers for widespread human use because of the possibilities
of mass production of the miniature chemistry sets under
sterile conditions much like other medical devices such as
7. Concluding remarks syringes.
The other area ripe for exploitation is in achieving higher
Table 8 illustrates the vast variety of uses for radioactive specificity of the tracer. This will most likely occur in the
substances, some of which are obscure while others are use of peptides (protein fragments) and oligonucleotides or
essential in modern life. The list is not comprehensive and short strands of DNA, which will be specific for a particular
only represents those associated with life sciences. An equal gene expression for protein syntheses related to pathological
list can be generated for the physical sciences. conditions. Being able to clearly identify a phenotypic disease
The future in imaging now lies in the development in a population could overcome some of the shortcomings
of multi-modality imaging approaches such as PET/CT, related to PET’s lack of sensitivity. Having a tracer that has a
SPECT/CT and PET/MRI, as well as the use of optical very high signal relative to the background enhances the ability

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Rep. Prog. Phys. 72 (2009) 016701 T J Ruth

to detect small quantities, thus increasing apparent sensitivity. Health Canada 2005 Zevalin Available from:
In addition, this approach would truly introduce personalized http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/proj/
sbd-smd/nd ad 2005 zevalin 076192 e.html accessed January
medicine since the compounds used would be unique to the 15th 2007
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While the use of radioactive species has become associated with positron emission tomographic scanning of
widespread in the health field their use in other fields is still small laboratory animals Eur. J. Nucl. Med. 25 173–6
relatively rare. This review paper tried to illustrate the power Iwata R 2002 Reference book for PET radiopharmaceuticals
http://kakuyaku.cyric.tohoku.ac.jp/public/preface2002.html
associated with using radiotracers in a variety of disciplines, Judenhofer M S, Catana C, Swann B K, Siegel S B, Jung W I,
both in basic research and in practical applications. While most Nutt R E, Cherry S R, Claussen C D and Pichler B J 2007
of the non-medically related applications of radiotracers have PET/MR images acquired with a compact MR-compatible PET
used reactor produced species because of their availability, detector in a 7-T magnet Radiology 244 807–14
Kawamura K, Elsinga P H, Kobayashi T, Ishii S, Wang W F,
the use of accelerator produced tracers has the potential for a Matsuno K, Vaalburg W and Ishiwata K 2003 Synthesis and
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