Radiopharmaceuticals and Other Compounds Labelled with Short-Lived Radionuclides

229 Pages·1977·6.77 MB·English

by  Michael J. Welch (Eds.)

Other Titles of Interest
J O U R N A L S
Applied Radiation & Isotopes
Computerized Tomography
Radiation Physics & Chemistry
Int. J. of Radiation Oncology-Biology-Physics
Int. J. of Nuclear Medicine & Biology
BOOKS
HEALY: Plutonium: Health Implications for Man
DEWHURST: An Introduction to Biomedical Instrumentation
HALL: Radiation and Life
KIEFER & MAUSHART: Radiation Protection Measurement
Radiopharmaceuticals and Other
Compounds Labelled with
Short-lived Radionuclides
Editor
MICHAEL J. WELCH
The Mallinckrodt Institute of Radiology,
Washington University School of Medicine,
St Louis, Missouri, U.S.A.
P E R G A M O N P R E S S
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First edition 1977
Library of Congress No. 76-26764
Published as a special issue of the International Journal of Applied Radiation and
Isotopes, Volume 28, Numbers 1/2, and supplied to subscribers as part of their sub-
scription.
Printed in Great Britain by A. Wheaton & Co. Ltd., Exeter
ISBN 0 08 021344 8
Editorial
NUCLEAR Medicine, which may be defined as the application of radionuclide techniques to the investiga-
tion of human disease, is a rapidly expanding speciality. All nuclear medicine procedures have two essential
requirements, an appropriate radiation detection device and a suitable radionuclide preparation or radio-
pharmaceutical. In general, the characteristics of the detection device determine the precision and sensitivity of
the procedure while the radiopharmaceutical determines the type of functional and/or anatomical information
which is produced. In recent years the increased availability of radionuclides of short half-life from generator
systems or from charged particle accelerators has led to a dramatic increase in both the types of radiopharma-
ceutical available and in the scope of the biomedical investigations available to the nuclear medicine physician.
In this Special Issue, our Guest Editor, Professor MICHAEL WELCH has assembled a series of papers, by many
distinguished authors, which review the current "state of the art" in the field of short-lived radiopharmaceuticals
and illustrate the exciting potential for radiopharmaceutical development.
DAVID M. TAYLOR
1
International Journal of Applied Radiation and Isotopes, 1977, Vol. 28, p. 3. Pergamon Press. Printed in Northern Ireland
Introduction
MICHAEL J. WELCH
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis,
Missouri, U.S.A.
ALTHOUGH two major1 2, publications on radiopharma- particular importance for these new labeled radio-
ceutical development* * have been published in the pharmaceuticals.
last few years, the field of nuclear medicine in general In this special issue, through both review and con-
and radiopharmaceutical development in particular tributed articles, potential applications and develop-
have been stimulated by the innovations in the field of ments in labeling with short-lived radionuclides
transmission computerized axial ( 3) tomography. As whose use is restricted to institutions with ac-
pointed out by TER-POGOSSIAN, "the strength of celerators are discussed. The current and potential
nuclear medicine can best be realized by the use of use of generator-produced radionuclides as well as
radiopharmaceuticals designed to identify function other radionuclides of half-life up to four days, and
rather than the more conventional armamen- the problems of quality control of such labeled
tarium." Although for function studies the ideal compounds are examined. A short half-life was
tracers are compounds labeled with the short-lived defined as four days in order to include indium-Ill
radionuclides oxygen-15, nitrogen-13 and carbon- and gallium-67, but to exclude iodine-131, whose
11, not all institutions have or are likely to own decay characteristics render the radionuclide less
accelerators capable of producing these radionuc- than ideal for in vivo use.
lides. To parallel developments utilizing the short- The contributions to this special issue illustrate the
lived radionuclides, therefore, work is proceeding exciting potential of radiopharmaceutical development,
on methods to label biologically active compounds despite the threat of transmission computerized axial
with more easily obtainable nuclides, such as tomography as an alternative to certain radionuc-
iodine-123, indium-Il l , gallium-67, gallium-68, lide studies. It is hoped that the compounds discus-
bromine-77 and technetium-99m. The work with sed will (b6) e utilized in spite of the concerns of
gallium-68 shows( 4t5h) e potential of the new positron- M C A F E E that the "regulatory crisis" is severely
imaging devices ' being used in institutions that limiting the approval of radiopharmaceuticals in the
do not have the capability of producing the short- United States.
lived positron radionuclides, oxygen-15, nitrogen-
13, carbon-11 and fluorine-18. These imaging de-
vices couple the advantages of tomography with the REFERENCES
ability to label compounds designed to measure 1. Radiopharmaceuticals and Labeled Compounds, Vol.
specific physiological functions. 1 and 2. IAEA, Vienna (1973).
Developments with other radionuclides appear 2. Radiopharmaceuticals (Edited by SUBRAMANIAN G. ,
directed toward the development of metabolic RHODES Β. Α., COOPER J. F. and SODD V. J.), Society
analogs. These include various technetium chelates, of Nuclear Medicine, 1975.
various agents designed to measure thrombolytic 3. TER-POGOSSIAN Μ . M. In The Year Book of Nuclear
activity and compounds specifically designed to Medicine 1976 (Edited by QUINN III J . L.) , pp. 9-14.
label blood cellular components. Year Book Publishers, Chicago (1976).
The development of radiopharmaceuticals designed 4. BURNHAM C. A. and BROWNELL G . L . IEEE
to measure specific functions needs a parallel develop- Trans. Nucl. Sei. NS-19-3, 201 (1972).
ment of techniques for the quality control of radio- 5. TER-POGOSSIAN Μ . M., PHELPS Μ . E., HOFFMAN
pharmaceuticals. Although pharmaceutical qualit(y2) E. J. and MULLANI N. A. Radiol. 114, 89-98 (1975).
control has been discussed in detail in the past, 6. MCAFEE J. G . Am. J. Roentgenol. 126, 908-909
measuring and ensuring radiochemical purity is of (1976).
3
International Journal of Applied Radiation and Isotopes, 1977, Vol. 28, pp. 5-11. Pergamon Press. Printed in Northern Ireland
Potentials and Problems of
Short-lived Radionuclides in
Medical Imaging Applications*
PAUL V. HARPER
Departments of Surgery and Radiology, The University of Chicago, and The Franklin
McLean Memorial Research Institute,! Chicago, Illinois 60637, U.S.A.
(Received 14 February 1976)
Various considerations involved with the production, processing and synthesis and applications
of short-lived nuclides are presented. In particular, the use of rapid synthesis and the unique uses
of short-lived agents to present static equilibrium images from which dynamic information can be
derived are examined. This approach appears in principle to be generally applicable in situations
where the physiologic processes in question have durations comparable to the half lives of the
nuclide used.
WHIL E many of the obvious advantages of short- pharmaceutical preparation, enter into the
lived radionuclides for imaging studies have picture and may become the dominating factors
long been appreciated, only recently have in particular situations. It has been proposed
applications been described in which the short that when an in vivo procedure is carried out
physical half-life is a necessary property for using a radionuclide, other things being equal,
making the measurement desired. Developments the time of the measurement following the
in the areas of production techniques, instru- administration of the nuclide should approx-
mentation, chemistry and clinical application imate the average life of the nuclide in order to
have usually gone hand in hand and these obtain the greatest information for the smallest
( 1)
various interdependent efforts are often difficult radiation absorbed dose. Unfortunately, the
to separate. decay rates of available radionuclides often do
Historically, during the past decade, the not match the time scale of the desired measure-
gradual replacement of 1 3 l l by 1 2 3I and ment. For instance, the long-lived, slowly
g9 e9 nmTerca0l p4 -u rfpoor steh ylarboeidl, wofo 8r5Sk,r abnyd 8 7bmyS 9r9,m T1 8cF ,a sa nthde reexacdreiltye da va7i5Slaeb-Lle- saemleino maceitdh iaonailnoeg, , itsh ue sedo nfloyr
by the 9 9 mT c phosphate compounds for bone short-term measurements. In addition, 1 3 3X e ,
1 2 7 2 0 3
imaging, reflects the effort to reduce radiation X e and H g chlormerodrin are examples of
absorbed dose and to increase photon flux in long-lived agents which are excreted rapidly.
order to improve image quality by making use This appears to provide substantial advantages,
of short-lived agents. i.e. long shelf-life, low radiation dosage. Such
Other dosimetric properties of the nuclide, i.e. applications however have substantial dis-
the presence or absence of particle radiations advantages, in that large amounts of long-lived
and the biological residence times of the radio- material are introduced into the environment
via the patient in a manner not always easy to
control. In addition, in these agents, minor
* This work supported in part by Contract NI HV- distribution components may have long
52980, Radiologic Imaging Center Grant 18940-04 and
residence times which may become the dominat-
SCOR-Ischemic Heart Disease Contract No. Hl-
ing factors in the dosimetry. This is particularly
17648. 2 0 3
t Operated by the University of Chicago for the true in the case of Hg-chlormerodrin. The
Energy Research and Development Administration use of short-lived nuclides avoids these difficulties
under Contract No. E(l l-l)-69. and reduces the contamination problems sub-
5
6 Paul V. Harper
( 6)
stantially. A major spill of a radionuclide with of CO 2 as aspartate has been attempted , and
even an intermediate half-life is a serious labora- it seems likely that the use of enzymes may
tory disaster, while with shorter-lived agents prove to be a generally useful approach either
this problem is greatly reduced. alone or in connection with organic methods
A number of elements of biologic interest have where it may, for instance be useful in introduc-
only short-lived radioisotopes. These are oxygen, ing an amino group to produce an optical
nitrogen, carbon and fluorine. The first three isomer directly. The fixation of oxygen-15 by an
of these materials require on-site production enzymatic method has become the routine
1 5
facilities. Sufficiently efficient production approach for making labeled 0 water by
1 8
methods for F exist so that an order of exchange in the presence of carbonic an-
( 7)
magnitude of physical decay during shipment hydrase. This method also works in vivo
1 5
can be tolerated; however, the expense involved since inhaled C 0 2 is almost instantly con-
1 5
for such "over production" is not trivial. The verted to H 2 0 when absorbed in the lungs. In
longest lived isotopes of the other substances are general, the enzymatic methods permit the pro-
1 5 1 3 n
the 2.0 min L , 10 min N and 20.4 min C . duction of very high specific activity products by
5
While a compact cyclotron ($5 χ 10 < cost the introduction of a high specific activity label.
6
< $1 χ 10 ), is the most effective production Additional chemical substances in the final
device for these agents in a medical environ- preparation consist only of the precursors,
ment, physics-oriented accelerators (tandem which, under these circumstances, are usually
Van de Graaff generators) have been used non-toxic metabolites. The removal of the
effectively when such equipment is available in enzyme by column chromatography or pre-
reasonable proximity to the user's location. cipitation is rapid and complete. If an im-
Modest energy and beam current requirements mobilized enzyme is used, this becomes un-
(10 μ A 6-8 MeV deuterons) are capable of pro- necessary.
ducing usable amounts of these agents, although
A more complex biological synthesis using an
( 8)
much more flexible and efficient production is
intact organism has also proved effective in
n
possible with multiple particle cyclotrons which
the production of C glucose.
are capable of producing curie quantities of
1 3 l 1 6 Efforts to speed up conventional organic
N and C by the (p,a) reaction on 0 and
1 4 1 8 2 0 methods such as the Strecker synthesis for
N respectively and of F by (J, a) on N e .
amino acids by using high temperature and
9
The need for efficient use of such materials pressure are likewise proving fruitful* * and this
has stimulated a growing technology for the approach, in connection with an enzymatic
rapid synthesis of radiopharmaceuticals. It is method to separate the resulting optical isomers,
usually necessary to administer several milli- is an additional promising option.
curies of an agent to achieve the desired result; Sometimes it has been found possible to make
thus preparation times of more than a few use of the reactions of radiation chemistry to
minutes result in significant decay losses which in produce a desired compound. A good example
1 3
turn require starting with a much higher initial is the preparation of N-ammonia by the
( 1 0)
activity with its attendant problems. While some deuteron bombardment of methane. The
organic syntheses are rapid, the Grignard systematic exploration of the effects of pressure
( 2)
reactions for instance, organic methods are in and composition in various gas targets is
general slow and alternative approaches have another approach which is being carried out. It
been sought. Enzymatic methods appear en- seems likely that this method will be useful only
couraging as they permit the rapid production of for rather simple molecular species.
fairly complex biological compounds in accept- Much of this effort is covered in recent ex-
( 1 1 1) 2
able pharmaceutical form. This has been done tensive reviews and conferences .
with nitrogen-13 compounds producing glut- The production of short-lived radionuclides
1 3
amate and asparagine from N ammonia and from generators has a long history beginning
2 2 2
alanine by transmethylation of pyruvate using with R n . The use of this approach has been
1 3 1 3 ( 3 _ )5
N glutamate as the N donor . largely responsible for the present popularity of
1 3 2 1 3 2
The use of enzymatic methods for the fixation short-lived agents. The T e - I generator
Potentials and problems of short-lived radionuclides 1
produced a 2.3 hr agent very useful for thyroid however, special collimation is necessary because
uptake measurements, but it was not until of the high energy 511 keV. This approach has
6 8 6 8 9 9 m 1 1 3 1 1 3 m
G e - G a , " M o - T c and S n - I m been extensively explored in connection with
1 8
generators became available that nuclear medi- bone imaging with F . Ordinarily a scanner is
cine turned substantially in this direction. the most efficient device to use because its thick
The availability of high activities which could crystal is more efficient than the |-in. thick
be administered with reasonable radiation doses camera crystal. Collimation of the high energy
led to developments in instrumentation to make radiation for a camera poses several problems.
use of these capabilities. The autofluoroscope Available lead collimators are either very thick
1 3 7
was developed to make use of the 2-min B a with low efficiency, or have thick septa with a
1 3 7
activity from the 30-year C s parent. The reduced number of holes which reduces the
thick crystals and parallel data acquisition efficiency and introduces a substantial hole
system were chosen to give high detector pattern into the final image because of the high
efficiency and rapid counting capability for intrinsic resolution of the scintillation camera
dynamic studies, design capabilities which are at this energy. Tungsten collimation is effective
only recently being approached by single crystal and reduces these problems somewhat, but is
1 6)
camera systems. The development of dynamic expensive/ Removal of the hole pattern from
heart imaging from radiocardiology using a the image has been possible by movement of the
single crystal detector to the multiple chamber collimator in a manner analogous to the Bucky
( 1 7)
dynamic analysis has put substantial pressure on grid. Pin hole collimation has been used
instrument manufacturers to increase data effectively.
acquisition and storage rates, which have be-
The improvement in energy resolution with
come the limiting factors in such studies. The
increasing energy permits effective removal of
entry of a number of new manufacturers into
the scattered photons from the positron an-
the camera field has produced a remarkable and
nihilation radiation arising in the source by
healthy competition and substantial technical
pulse height analysis, so that the effective source
improvement in these areas in the past few
contrast is improved over that obtained with
years.
lower energy gamma rays.
The introduction of the ultra short-lived, The detection of positron annihilation radi-
8 1 m ( 1 3)
generator-produced agents such as K r ation in coincidence provides a form of electronic
8 2 ( 1 4)
and R b , has introduced a further step in collimation which has additional advantages as
the direction of rapid imaging which is currently well as some limitations. The photon pair
being explored. originate at the annihilation event between the
1 5 1
Of the substances mentioned a b o v e , 0 , * C , positron and an ambient electron and leave in
1 3 1 8
N , F , and the two generator produced essentially opposite directions. The deviation of
6 8 8 2
short-lived nuclides, G a and Sr , decay by the angle between the two photons from 180° is
positron emission, so that comments on the approximately 0.6° due largely to the thermal
potentials and problems involved with positrons motion of the particles and constitutes the
are appropriate in the present discussion. principal intrinsic uncertainty in this mode of
Positrons, being particle radiation, result in imaging.
high deposition of energy in tissue where the A variety of configurations exists for coin-
source activity is located, so that the absorbed cidence imaging. The sensitivity is always in-
dose is intrinsically fairly high even with a trinsically low in spite of the absence of
short half-life material. The positrons travel a mechanical collimation because of the require-
short distance in tissue before slowing down to ment that both photons of an annihilation pair
thermal energy where the annihilation process, must avoid scatter or absorption in the object,
for the most part, occurs. The path length results and both must be detected in the instrument to
in a small apparent broadening of the effective produce a proper detection event, and this must
( 1 5)
object distribution of the nuclide. Detection be accomplished against a background of un-
of the annihilation radiation with ordinary wanted primary and scattered radiation, which
gamma imaging equipment may be carried out; give rise to random coincidence events due to
8 Paul V. Harper
the non-zero width of the timing windows. As a The necessary conditions to be met under these
result, serious count rate limitations exist in circumstances is that the physical decay time of
such a system, which only recently have given the agent should be of the same approximate
way to some extent to instrumental develop- magnitude as that of the physiologic function
2 5 3 0)
ment. This has been accomplished by using under investigation/ "
multiple detectors to increase the effective solid For example, consider in a simplistic way the
angle of acceptance so that the count rate limit- blood flow into a tissue volume of interest at
( 1 8 , 1) 9
ation in any one detector is small ; or, in equilibrium. The quantity of activity in the
20 2 υ
the case of the single crystal camera system* ' volume Κ may be determined from quantitative
by limiting input singles counts by excluding reconstructive imaging methods to be Q. Since
scattered radiation using graded absorbers and Q at equilibrium is constant, the amount of
by using fast-slow coincidence to eliminate most activity entering Κ and leaving F must be equal.
of the remaining unwanted singles events prior The amount entering via the blood stream is the
to the slower pulse positioning operation in the arterial concentration C times the flow F. This
a
camera analogue network. These various must equal the loss by physical decay plus the
approaches have succeeded in making positron amount leaving by washout and failure of
coincidence imaging reasonably competitive extraction.
from the count rate point of view.
This relation may be expressed as :
The principal intrinsic advantage of positron
coincidence detection is that since it deals only
with unattenuated radiation from the source
where Ε = extraction ratio, λ is the physical
Β
distribution, the results obtained are depth
decay constant and λ„ is the (mono)exponential
independent. Moreover, the best resolution of
washout constant.
such a system is, from geometric considerations,
Implementing this for ,a diffusible tracer, say
at a point midway between the detectors rather 8 2
S r , in the myocardium, the washout will be
than at the camera face as with the ordinary
very slow compared to the physical decay so
gamma camera. As a result, reconstruction of a
that X becomes negligible. Assume an extraction
w
radionuclide distribution by any of the various
ratio of «0.7:
available methods becomes much more readily
possible, free from the effects of attenuation, and
when normalized against a transmission image Then
is capable of giving quantitative results when
compared to a standard source.
The use of quantitative reconstructive imag-
ing appears at first to be incompatible with the
use of short-lived or ultra short-lived agents
Perfusion, F/V Ä 0.8 (C/C ) where C = Q/V the
t a t
because high count density records are in general
concentration in the tissue of the myocardium.
required for such applications. This incom-
The ratio CJC should be measurable in the
a
patibility vanishes however, when equilibrium
( 2 2 2 4) image with fine enough 3D resolution. If F/V is
images are used . '
assumed to be normal, i.e. ~ 100 ml/min/100 g,
Furthermore, the administration of a short-
then Ct/Ca Ä 1.2; at 50 ml/100 g, CJC
a = 0.62,
lived nuclide by whatever route until a steady
assuming the extraction is unchanged. Thus the
state is achieved results in a situation where
ratio CJC appears to be a sensitive measure of
a
dynamic biological parameters may be deter-
perfusion.
mined from the steady state parameters of the
In the case where a rapidly diffusible tracer is
1 5
equilibrium. Since the steady state may in
used such as H 0 where the washout is rapid
2
principle be maintained indefinitely, no time
and Ε may be assumed equal to 1, the balance
limitation is introduced and conventional
equation is :
7
stationary imaging approaches may be used in-
cluding quantitative reconstructive methods.
This approach is unique to short-lived emitters. since Àw = F/V assuming equal partition of the
Potentials and problems of short-lived radionuclides 9
tracer between blood and tissue, F=Q\
D/ Krypton-79m, although the low abundance of
[C
a ~(Q/ V)] and since Q/V= C„ the tissue con- the krypton radiation would require the use of
centration of the tracer, perfusion = F/V = A
0/ solid state detectors in order to resolve the
[(Co/O-l]. 127 keV photopeak from the background
1 5
For 0 , T = 2.03 min CJC « 1.34 in the continuum.
1 /2 t
normal myocardium for Fj V = 100 ml/m/100 g. In general, as illustrated in the above examples,
For F / F = 50, C, /C
e= 1.68. If the ratio Ct/Ca when the introduction of the label is independent
can be measured in the image with fine enough of flow the longer half-life will produce greater
3D resolution, it should also provide a measure of object contrast with respect to flow. When the
regional perfusion. This might be made more introduction of the tracer is dependent on flow,
1 4
sensitive by using 0 , T 1.18 min. The the shorter half-life agent will give a result more
1/2
corresponding values of CJC are then 1.58 for sensitive with respect to flow.
a
F / F = 100and2.17forF/F= 50. Combining the The generalization of this type of approach to
8 2 l 5
results from R b and H
2 0 in principle any form of physiological turnover appears in
permits determination of the distribution of principle to be possible.
rubidium extraction, although it does not seem The simultaneous administration of the two
1 4 1 5
likely that at the present state of the art oxygen isotopes 0 and 0 has been used to
sufficiently precise measurements are possible. estimate the transport of oxygen to different
An implementation has been described in the parts of the body by measuring the ratio of the
( 3 3)
lung (without the reconstruction) by FAZIO and two isotopes as they decay at different rates.
( 3 )1 8 1 m
J O N E S using K r administered contin- For routine application of a short-lived agent,
uously by inhalation to define the average one of the principal requirements is a reliable
regional turnover (ventilation) in different source of supply. In a practical context the use
regions in the projected lung image, and a of short-lived agents in critically ill patients
similar approach has been used to measure imposes substantial logistical problems, al-
( 3 2)
cerebral blood flow in children. though the capability of making sequential
A somewhat different implementation is measurements to follow the course of a disease
11 3)
described by JONES and M A T T H E W S in which process or to observe the effect of stress on
8 1 m
the introduction of the short-lived agent K r thereapeutic efforts would seem to be one of the
is independent of flow, resulting from the decay main clinical advantages of short-lived agents.
8 1
of the parent R b lodged in the tissue. Here Measurement of regional cerebral blood flow,
8 l m
the rate of appearance of the K r is proportion- in the presence of serious head injury, for
8 1
al to the amount of R b present which may be instance to determine progression of change due
monitored independently. The observed para- to swelling, while not at present a routine pro-
8 1 m
meter, the concentration of K r in tissue in cedure, certainly appears to be a desirable goal.
equilibrium with its parent, is dependent on Dedicated or mobile equipment and an available
8 1 m
flow. In the absence of flow, the K r dis- supply of radionuclide for such a process would
appears only by physical decay while in the be necessary on short notice. A possibly viable
presence of flow it is also washed out. Thus option in this situation would be the availability
8 1 8 1 m
ρ = X Q + X^j) where Ρ is the production rate of a R b - K r generator to be used routinely
D
8 1
proportional to [ Rb]. In the absence of flow during the day for lung studies and available
k = 0, so that otherwise for cerebral flow studies. Intra-
w
arterial injection would be necessary in the left
A A v ventrical or root of the aorta. Ordinary static
inflow 0 D
images in the usual projections should give a
Under these conditions, a normal myocardial reasonable estimate, although not quantitation
8 l m
flow will reduce the K r level in the equilibrium of the relative regional cerebral blood flow.
image about 25% below the no-flow level. To use the more sophisticated option of
7 9 7 9 m 1 5
The use of the 24 min R b ->55 sec K r H 2 0 as a diffusible tracer administered as C 0 2
would make this approach much more sensitive to produce an equilibrium state which could be
to flow because of the longer half-life of the displayed by reconstructive techniques would