edited by: MICHAEL R. SLABAVGH HELENJ. JAMES Webw State College 4
chem I mpplement
Ogden. Utah 84408
Diagnostic Radiopharmaceuticals N. Foster Department of Chemistry and Center for Health Sciences, Lehigh University, Bethlehem. PA 18015 Life is a well-orchestrated series of dynamic chemical events, disease disrupts the harmonious interplay. Physicians can now view the vhvsioloeical ~rocesseswithin livine organisms through a number of "wfndows" and thereby assess the nature of health and the status of disease noninvasivelv. One of these windows is provided by nuclear imaging with radiovharmaceuticals. The term radio~harmaceuticalhas bern k e d to identify several types of radioactive compounds used clinirally, but for the Durooses of this review only those compounds administered t o patients to ohtain diagnostic information will be discussed. Radiopharmaceuticals are radioactive agents which selectively localize in specific target areas within an organism. This selective localization enables a physician with an appropriate radiation detector to generate a picture or "image" of the area in which the ~harmaceuticalconcentrates. From such images ~ ~ - - insights i n t i both the static and dynamic structure and function of hioloeical mav. he eleaned without re- Drocesses . sorting to surgical techniques. Studiej using radiopharmuceutical methodolories have orovided nrtuallv all iniorniation now known about the physiology and pathdlogical states of or~ans.tissues, and vrocesses. as well as about normal metaboiic pathways in both and animals. ~
-
~
~
~
--~
~
~~~
~
Early Studles Using Radlolsotopes Radioisotopes have been used in evaluations of human physiology since Seil in 1914. ir scant 19 years after the discovers oi radioactivity, studied the appearance of radon in the breath and radium in the excreta ofvolunteers injected with radium salts ( 1 ) . One year earlier in 1913 George Charles de Hevesy, who would later be acknowledged as the father of nuclear medicine, and Fritz Paneth used a lead isotope as an "indicator" for lead in an experiment to determine the solubilities of lead salts in water ( 2 ) .Thus, the tracer concept was established: a radioactive atom may he used as arepresentative "tracer" of the behavior of stable atoms of the same element in chemical systems. In later years Hevesy would use radioisotopes in biological systems as well, thereby paving the way for the use of isotopes in medicine. To study the circulation of lead in plants, Hevesy measured the radioactivity in parts of plants after they had taken up radioactive lead; he was
~
able not only to quantify the absorption of lead but also to determine its hiodistrihution. His detection method (a gold leaf electrosco~e)was so sensitive that he could use miniscule quantities of iadiolead and thereby avoid any toxic effects, a Dossibilitvwhich mints to another advantage of radiotracers 3611capitahzed upon in modern nuclear mehicine. 'I'he iirst clinical studies invulvine. radioactive wacers were conducted in Boston in the late 1920's when Blumgart and co-workers iniected solutions of bismuth-214 in one arm of volunteers and detected with a cloud chamber the emission uf gamma rays from the other arm. By noting a normal armto-arm blood rirculation time of 18 sec, they would later observe that circulation required a longer time in patients with heart disease (4). The discovery hy Irene Curie and Frederic Joliot in 1934 of artificial radioactivity-that nuclear bombardment of stable atoms could transmute some light elements into radioactive forms of other elements-ooened the door to the production of an ahundance of usefui rirdiotracers. In 1935 Chiewitz and Hevesv (51 reooned the first classic indicator . study with a radioactive form of phosphorus, an essential element in the animal svstem. Usine a Geieer counter as a detector, they observed-phosphorus-32 uptake in organs and tissues after feeding rats phosphorus-32 sodium phosphate. The results strongly supported their view that "the formation of bones is a dvnamic Drocess, the bone continuouslv takine up phosphorubatotns which are partly or wholly lost again a n i replaced by other ~ h o s ~ h o r atoms." us The dvnamic state of bddy cons&tueng wa; further established by many other isotope experiments which eventually lead to the concept that the apparent stability and constancy of the body is a result of a delicate balance among innumerable chemical reactions occurring simultaneously~(6). These seminal studies from the early days of research in the life. The information presented might be used directly in class, posted on bulletin boards or otherwise used to stimulate studem involvement in activities related to chemistry. Contributions should be sent to the featureeditors.
Volume 61 Number 8 August 1984
689
RadionuclldesUsed in Radlopharmaceuticals
application of radiotracers to studies in physiology have established the fundamentals that are still applied rationally today in the search for and use of diagnostic radiopharmaceuticals. Tracer methodology, when coupled with the recognition of the dynamic nature of the body's components, has lead to the fruitful and revealing examination at the molecular level of virtually every physiological process. Figure 1shows a modern example of the use of a radiolabeled substance to study the dynamicprocess of blood flow in the hrain. All Radionuclldes Are Not Created Eaual All radionuclides are not suitable for use in radiopharmaceticals. For the best imarinr nuclides should possess - -aualities, . either a gamma emission with an energy hetween 20 and 600 keV or a positron emission. Of course, the t w e of emission will determine the detector that is required, and-each detector will have ita own "most useful range" of energy quantification. The physical half-life of the radionuclide shwld also be as short as possihle while still permitting the acquisition of the desired diagnostic information. The range that often has been cited as suitable is a half-life between 1 hour and 1 year (7). The half-life must beshort tominimize the radiation dove to the patient, hut it must he long enough tn prevent a n~ultitude of technical oroblems. Technical difficulties are caused bv a nuclide withAashort half-life if the shelf-lifeof the agent i;so hrief that the material must be prepared several times adav: if it is too hrief, the long time hisiribution studies, delayid studies, or sequential evaluations crucial to the diagnosis of certain disease states may be impossible. Difficulties may also result if the half-life is too hrief because any necessary synthetic modifications involving the nuclide will have to be very fast, selective, and efficient. Thus, one needs isotopes emitting the proper energy with half-lives as short as possible to minimize radiation load to the patient but not so short that they interfere with the diagnostic usefulness of the procedure.
Oamma E m M
690
Journal of Chemical Education
iodine-123 iodine-125 iodine-131 selenium75 bromine-77
13 h 60 d 8.05 d 120 d 57 h
nuclMe carbon-1 1 nilrogen-13 oxygen-15
half-life 20 min 10 mln 2 min
nuclirk, lhallium201 technetlum99m indium1 11 indium1 l 3 m
half-life 73 h 6h 2.8 d 110 mln
PosWon Eminem llllclirk,
gallium-88 fluorine-18 bromine75
half-life 68 min 108 min 95 min
Common radionuclides used in diagnostic radiopharmaceuticals alone with their half-lives are summarized in the table.
-
Categories of Radlopharmaceuticals Radio~harmaceuticalsmav be as chemicallv simole as the radioactive gases xenon-133 br krypton-8lm,;ons iike technetium-99m ~ertechnetate(TcOd-), com~lexesof radioactive metals like tkchnetium-99m or indium-ill with organic ligands, or organic molecules containing covalently bound radiohalogens, carbon-11 or selenium-75. Whatever its chemical identity, the radioactive compound may he classified according to the mechanism hy-which it concentrates in the target organ or tissue as either substrate-nonspecific or suhstrate-spkific (8). Category I-Substrate-Nonspecific In the substrate-nonspecific category are substances whose localization does not depend uoon a specificchemical reaction. Most current clinicall~usefu~radio~harmaceuticals fall into this category. For example, a lung scan to detect pulmonary emboli may he performed by injecting particulate microspheres crafted from human serum albumin and technetium99m. These microspheres, which average about 20 microns in diameter, block off a portion of the lung's capillary bed and thereby image the distribution of arterial hlood flow in the lunas. Abnormalities in distribution of the micrm~heres show up & the image as areas of diminished or absenGadioactivity and correspond to areas of structural or functional within the lungs. In the quantities required for an accurate scan, 0.1% or less of the vessels in the lungs are blocked; the net effect on pulmonary circulation is nil (9).The key to the substrate-nonspecific classification of this agent is that regional hlood flow is being measured by capillary blockage, but the agent used to block the ca~illariesneed not ~ : particulate be a specific substanre, only a specific ~ 1 2Any radiopharmaceutird of the correct size could he applied to this imaging task. Figure 2 shows a typical lung sc& done with a substrate-nonspecific agent. The cells of the reticuloendothelial system (RES) like the liver and the spleen are identified by their ability to ingest colloidal and particulate matter by means of a process called phagocytosis. Radiocolloidsthat have been developed for liver and spleen scanning include Au-198 colloid, Tc-99m sulfur colloid, and In-113m colloid. Once again, the chemical identity of the colloid and its radiolabel are not important, as long as the size (about 1 p ) is appropriace to he phagocytized byihe cells of the orean of interest. After administration of the colloid, the images of the RES show areas of radioactivity (hot spots) where the organ is functioning properly and the cells are ingesting the colloid and no radioactivity or diminished activity (cold spots) where no Dhagocvtosis is occurring. The scan thereby Govides significant E ~ i i i c ainformationahout ~ the pathological condition of these organs. In contrast to the capillaries of most tissues of the hody which are penetrated easily by ions, the capillariesof the brain are much less permeable. The so-called blood-brain harrier, ~~
Figure 1. The use of oxygen-15-labeled water, injected intraveneously. to measure cerebral bioad flow. The images are oriented such that the left side 01 the brain is tothe reader's left and the anterior of the brain is up. The image on the left is normal: the imageon the right shows the result of electrical stimulation of the median nerve. The very bright, pronounced area on the ien side of the brain during stimulation is due to the dramatic localized increase in blood fbw. Photo Courtesy of Dr. Marcus E. Raichle. Professor of Neurologyand Radiology. Washington University Schmi of Medicine and the Edward Mallinckrdi InstitUte of Radiology, St. Louis. MO.
half-life
n"cI&
~
~
~~
which is actually a formidable nonpolar memhrane, protects the brain from materials carried in the bloodstream (10).The sites of tumors and vascular lesions in the brain are areas where the blood-brain barrier is usuallv imnaired: hlood-borne radiopharmaceuticals may readily enier these abnormalities which mav then he imaeed as hot soots on an otherwise cold scan. ~h'identity of tKe radiophknaceutical used in this context is unimportant, as long as i t is normally not capable of crossing the blood-brain barrier. Technetium-99m pertechnetate, administered as NaTcO.,, is a common agent used because of its favorable half-life, its high blood solubility and its excellent clearance from the hody. Figure 3 shows a brain scan done with a technetium-labeled agent. ~~
~~
~~
Category 11: Substrate-Specific Radiopharmceuticals Although the use of suhstrate-nonspecific radiopharmaceuticals makes possible the study of certain phenomena, many researchers believe that further advances in the use of radiotracers in medicine will he accomplished only through the development of suhstrate-specific radiopharmaceuticals-agents that are chemically involved in defined hiochemical or pharmacological processes (8). Much past research on the evaluation of radiopharmaceutical imaging
aeents has involved attemots to lahel such substrate-soecific b~ochemicals(like amino-acids, hormones, metaboli'c suhstrated or comoounds of known ~harmacoloeicalactivitv (like drugs) with a radionuclide. r he rationales?or hoth ofthese a t t e m ~ tare s closelv related. m;tnufnrtured, utilized or stored in a It a'biomolecttl~~~is uarticular site, it tnav he lorical t o assume that if some of that molecule were administered to the living system, i t would likely localize in those same areas of production. use and storage. B4 the same token, if a compo&d exerts pharmacological effect in a tissue or organ, i t may he logical (hut not necessarily valid) to assume that the compound localizes in that tissue or organ. The similarity of approaches in these two cases lies in the reasons for the selective localization or distribution that can be best illustrated by several examples. The simolest form of suhstrate-soecific involvement is illustrated by iodine, perhaps the first radionuclide of the suhstrate-specific class used clinically. Iodine is utilized within the thyroid gland in the synthesis of the essential hormones thyroxine and triiodothyronine. Radioiodine is taken up in the thyroid for the same purpose. Consequently, primary and metastatic tumors and lesions of the gland may he detected on thyroid images as a result of the differential uptake of radioiodide in patholoaicallv - .involved tissue compared to norma1 - ~ tissue. ~ ~ ~- - - ~ ~ . ~ A more refined example of suhstrate-soecific association is found in the search foLimaging agents f i r kidneys. The use of mercury197 or mercury203 chlormerodrin (I)as a kidney imaging agent is a logical outgrowth of the use of the nonradiolaheled agent as a diuretic. Mercury chlormerodrin is quickly hound to proteins in the proximal and distal tubules in the kidneys and exerts a diuretic action. Radiolabeled chlormerodrin, administered a t doses well below those necessary to produce a physiological effect, hinds t o these same functionalities and enables the visualization of kidney structure.
a
The adrenal glands, which sit atop the kidneys, are divided into two different areas of function. The adrenal medulla is
,,,, D Figure 2. Normal lungs (scans A and B) and abnormal lungs (scans C and D) as imaged by technetium-99m macroaggregated albumin. Images A and C are anterior views of the lungs, while Band D are posterior views. The vastly diminished activity in the right lobe of the abnormai lung is clearly evident in Comparison to the normal lungs. Photo courtesy of Dr. Robert Wallner, Hahnemann University-School of Medicine. Philadelphia. PA.
C
D
Figure 3. Normal and abnormal brains as scanned with technetium-99m giucahsptonate. Scans A and B show a normal brain viewed from the posteriaand the right side respectively. Scans C and D (same orientation) show clearly an abnorwlity as adark spot in the right rear portionof the brain. Photo courtesy of Dr. Robert Waliner. Hahnemann University-Schwl of Medicine, Philadelphia, PA.
Volume 61 Number 8 August 1984
69 1
the interior portion of the gland where catecholamines, important neurotransmitters, are synthesized and stored. The exterior portion of the gland is the adrenal cortex, which biosynthetically converts and stores steroids and their esters (11). Structural or functional lesions of the adrenals lead to Addison's disease or other adrenal insufficiencv- -oroblems. Adrenal-imaging agents that would enable the noninvasive exploration of the glands have been sought among radioiodinated analogs of the natural catecholamines norepinephrine and epinephrine without success, but a carbon-11 dopamine (IIb) has shown promise as an adrenal-imaging agent. ~teroids and their biochemical precursors have also been evaluated as adrenal-cortex-specific radiopharmaceuticals. The uptake of a series of selenium-75 steroids has been studied, and selenium-75 labeled 6-P(methyl seleno)methyl-19-nor-cholest5(10)-en-3P-ol (IIa) is presently marketed in Europe as a useful agent for the diagnosis of a variety of adrenal diseases (12).
fl
HO
1
110: 6B-(MethyM~~~)~~th~~-19~~~-ebeb11t-5(10).en.3~.~i
Im: Carhn.11
labeled dopamine
A Special Category: Receptor-BindingRadiopharmaceuticals
The most elegant examples of substrate-specific radionharmaceuticals are the recentor-bindine-comoounds. Gen. krdly the accumulation of a compound in a tissue is a consequence of the material's lipid solubility, size, charge, or other physical property. However, in some cases of localization, the molecule binds to a structurally specific receptor in the target tissue. In the classical sense, a receptor is a discrete site with a specific three-dimensional molecular structure with which a b:lologically active compound interacts to initiate aphysiological response. Neurotransmitters, hormones, and probably many drugs exert their effects by virtue of their interactions with receptors. Receptors are critical sites for the transmission of chemical signals which regulate the normal functions of the body. The ahility to identify the nature and hehavior of receptors provides revealing information about various processes and disease states. If one can label a receptor-specific compound, then the measure of radioactivity in the area of localization will provide a picture of the receotor and vitalitv in . .~ooulation . that area. ' In adantine . a comnound for a receptor-bindine studv... the synthetic chemist views a receptor-specific molecule as consistine of two reeions 1111).One Dart of the molecule is the binding or essenGal site which inieracts directly with there-
ceptor; the other part is the modifiable or nonessential site, which is uninvolved in binding and therefore may be structurally altered without influencing the ability of the molecule t o react. Actually it is quite rare that enough information is known about the architecture of the receptor site to permit the tvDe of directed svnthesis imdied here. In nractice. two apprbiches are possibie to label acandidate receptor binding radiopharmaceutical. In the first approach, a radioisotope is incorporated in the candidate molecule in such a way as to minimize any structural changes. Isotopic substitution-the replacement of a non-radioactive atom in the molecule hv its radioactive isotope, like a carhon-11 for a carbon-12-is the simplest way to accomplish this. The lack of appropriate isotopes and the svnthetic difficulties make isoto~icsubstitutions for the synthesis oigamma-emitting diagnojtic radiopharmaceuricak only occasionallv feasihle. Admittedlv tritium as an isotooic replacement for hydrogen can be efficiently incorporated into many molecules by several synthetic methods. Tritium-labeled materials have been extraordinarily useful for determining sites of accumulation, receptor binding, biological half-lives and rates of excretion for many substances in experimental animals. However, tritium-labeled substances have no utility as in vivo radiodiagnostics because the weak beta emission of the nuclide cannot pass through - tissue to be detected. The next best attempt is bioisoteric replacement, a concept that has often heen used in drug development. One replaces an atom or xroup of atoms on the natural substrate for the receptor with another radioactive atom or group that is similar in size. For example, the replacement of a fluorine for a hydroeen has been studied. Recentor-snecific molecules have been labeled with fluorine-18 the hope that the binding ~rooertiesof the molecules so labeled would not be altered bv this iuhstitution. Along the same lines, a large number oisrlenium-75-labeled radiooharmaceuticals have been nrenared as analogs of sulfur compounds. Bioisosteric replacement of iodine for methyl groups, sulfur for methylenes and -SH for -OH have also been successful. Isotopic substitution has been applied to the synthesis of compounds for imaging neuroreceptors. The majority of therapeutically useful psychoactive drugs are thought to exert their effects by interacting with one of the many varieties of receptors for neurotransmitters in the brain. For example, the
. .
E.
892
Journal of Chemical Education
va: Pimozide
mechanism of action of the antipsychotic drugs (phenothiazines like chlorpromazinr and buiYruphenon& like spiroperidol, 1Va and 1Vh) is thought to he rrlated to their ability to hlwk dopamine receptors in the brain. The direct laheling of dopamine receptor sites with radiolaheled neuroleptic drugs is being performed to study these receptors in animals and humans. Compounds selected for labeling include spiroperidol, labeled with C-11 or F-18, and pimozide and haloperidol with F-18 (Va and Vh); these are used in the in vivo mapping of cerebral receptors in humans. A tritium-labeled spiroperidol has been used widely for localization studies in animals. Postmortem studies of brains from patients with various diseases have nrovided clues that mav indicate that certain changes in reriptors are relatrd to andmay even br the cause of some neuro~svrhiatrirdisorders. Patients with Huntington's Chorea show a decrease in the number of dopamine receptors in the caudate nucleus of their brains, whereas srhizophrenic patients show an incrrasr. The interpretation of the significance of these clues may be difficult, however. because the drugs patirnts have received may also have altered the number of receptors. In particular, haloperidol ( n drug used widely to relieve schizopl&enics)can increase the numb& of dopamine receptors. At any rate, the ability to measure the number and type-of receptors by the application of substratespecific radiopharmaceuticals has opened new dimensions for examination of the normal and dvsfunctionine brain (14). The second approach to the design of receptor-specificradionharmaceuticals is to attach a radionuclide to the modifiable portion of the molecule. One simply does not know in advance the structural features necessary for binding several different isomers which vary only in the locusof attachment of the isotope. They mav-hr svntheswrd first and then bindinr . can be ev&ated.- By observing the changes in avidity of binding caused by the structural alterations, one may establish the essential features for receptor-substrate interaction. The work on imaging estradiol receptors is a case in point. Receptor proteins have been found in target tissues of all known steroid hormones, and the importance of the estradiol receptor for treatment and prognosis in patients with primary and metastatic tumors of the breast is well established (14). Tumors with an increased number of estrogen receptors are more likely to respond to either additive or ablative endocrine therapy than tumors with few estrogen receptors. Attempts have been made to label estrogen analogs for the in vivo study of estrogen receptors in humans for the obvious diagnostic application. Studies are currently underway to determine the molecular architecture of the steroid receptor. Knowing the structural requirements of such receptors in detail will ulti-
mately lead to the directed synthesis of more effective receptor-specific agents (15). A wide variety of diseases and disorders are now characterized by changes in receptors. Several kinds of cancer, diabetes, metabolic heart disorders and heart attacks, obesity, Parkinson's disease, Alzheimer's type dementia, Friedreich's ataxia, and myasthenia gravis are currently thought to be involved with alterations in receptors, and the list of additional maladies increases daily (14). From the concept of rec e ~ t o rbindine radiotracers mav vet come the broadcast spectrum ulpotential diagnostic imaging agents. Hadiooharmaceu~icnl~ rwovide onlv one wav for ~hvsicians to gain information nonikasively about the str&;re and function of organs and processes. Comnuterized axial tomography (CAT)is a fir& established diagnostic technique, and recent advances in medical imarinr NMR ~rornisestill another powerful tool to aid physic&sin the& assessment of health problems. No one single methodology will provide all the answers to the myriad questions about the disease state. Radiopharmaceuticals, CAT scanning, and NMR each provide a unique perspective and enable the delineation of different problems. These tools of medical science must he used in a complementary manner to secure the most reliable, accurate information possible. Selecting the right tool for the job a t hand is more important than ever when the question is one of health, and for answers that involve physiological structure and function the right tool is often a radiopharmaceutical.
-.
~
~
~~~~~~~~~~
Literature Clted
G.. Wagner, H. N.. Jr.,"Hw it Began,"in'"NuclearMedicine," (~ditor: Wwner,H. N.,Jr.l,H.P.PuhlhbingCo.,bc,1976.p.6.
(1) Meyers, W.
(2) Hevesy, G.,Paneth, P.,Z A n o q Chem., 82,323(19131. (3) Hevesy. G..Biachem. J., 11,439 (1923). (4l Blumgart, H. L., Yem, 0. C., Amer. J. Physiol.. 72,216 (1925). ( 5 ) Chiewitz, O., Hevesy, G..Noturo, 136,754 (1935). (6) Wagner, H. N.. Jr.. "Outline of the Past and Future of Nuelem Medicine,"Ch. 1, in "The ChemistnofRadiophmsceutieals." (Editor: Heindel, N. D., Bwm, H. D., Honds, T.,Brady. L. W.). Mamon Pub. USA. Inc, NewYork, 1978,p. 4. (7) Burns, H. D., "Deaign of Radiophmceuticala," Ch. 3 in (61, p. 37. (81 &kolman.W.C.,Reha,R.C..J. N u d M d . l9,1179(1978). (9) W w e r , H. N., Jr., '"The Pulmonary Circulation," Ch. 12 in ( I ) , p. 123. (10) Taylor, J. B.. Kennewell, P. D., "Introdudary Medicinal Chamistry, EEU Horvood Ltd.. H A B d Press: A Division of John Wiley and Sons. Inc, New York. 1981. PP.
65-67.
~
~
(11) G d m a n , L. S.,Gilman, A. (Editara),'"ThePhanoamlgieal Baais of'rhorapeutica." 3rd ed.. Maonillan Co.. New York. 1965,p. 1612.
(121 Koapp, F.F.. Jr.."Selcnium and T~lluriumas Cabon Subatitutea," Ch. 16 in "Rsdiopharmaceutieals:Smdure-Adi~~Relatiimhip~.Witor:S~~~,RP.~,G~e and Stratton, Inc., New York, I981.p. 352. I131 Fmst, J.J..Kuhar.M. J.,''h V i t t t t t d InViiiLsbelingof NeumttttitteteReeep. tnra." . . ~ Ch ...... , 19 in i l I \ S W ~ (141 C ~ h w n 1 . 1. F .'qunn~iut8,cChanger in RReptor Cvnanlralrons ru a Punnm 01 D#arm."Ch. 9 ,n HcceptorHmdmg Xadmrraars..' Vol. I!, tFdrtnr Frkclman. W C . C R C Prr.?. I w R a a Rawn. FL.1982.p~.185.208. t151 Kstunelknk~n..i. A . Hieman. D. F . Carlson. K E .and I.lovd. J. F.."ln V i ~ a o d ~
~
.
Volume 61 Number 8 August 1984
693
