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Chapter 28. New Directions in Positron Emission Tomography-Part II
SECTION VI. TOPICS IN CHEMISTRY AND DRUG DESIGN Editor: Fredric J. Vinick, Pfizer, Inc., Central Research, Groton, CT 06340 Chapter 28. New Directions In Positron Emission Tomography-Part II Joanna S. Fowler, Alfred P. Wolf and Nora D. Volkow Chemistry and Medical Departments, Brookhaven National Laboratory, Upton, N.Y. 11973 Introduction - Positron Emission Tomography (PET) is a unique tracer method which can be used to measure the spatial and temporal concentration of radioactivity in a volume element of tissue in a living system (1). Because most PET radiotracers are labeled with "physiological isotopes" such as carbon-I 1 (t1/2: 20.4 rnin), fluorine-18 (t1/2: 110 rnin), oxygen-15 (t1/2: 2 rnin) and nitrogen-13 (tl/2: 10 rnin), there is great chemical flexibility in designing and synthesizing such materials to probe specific biochemical transformations. The method is exquisitely suited to the study of organic molecules such as therapeutic drugs and substances of abuse whose intrinsic spatial and temporal distribution are of scientific and clinical interest. The research potential of PET has hardly been tapped by the pharmaceutical industry. PET can be extremely valuable in the quantitative determination of the biodistribution of drugs in man and their short term pharinacokinetics in any body tissue. No other technology is capable of answering these questions as quickly, as safely and as precisely as PET. Part I of this review described the PET method and its recent use in studies of the brain, metabolism, heart disease and tumors (1). This chapter covers PET studies with therapeutic drugs and substances of abuse, and the rapidly emerging use of PET in clinical diagnosis. PET STUDIES OF THERAPEUTIC DRUGS AND SUBSTANCES OF ABUSE Druq Effects on Metabolism and Neurotransmitter Activity - PET has been mos widely applied to the study of CNS drugs. The 2-deo~y-2-[~~F]fluoro-D-glucose (1, ISFOG) (and also [ l - ' 1C]2-deoxy-D-glucose (2, l1C-2DG)) method is commonly used to measure regional brain glucose metabolism and the oxygen-I5 water method to measure regional brain blood flow (2,3). These tracers have been used to study the effects of acute as well as chronic drug administration on regional brain metabolism and blood flow. For example, the influence of neuroleptics (4,5), amphetamine (6), alcohol (7-lo), azidothymidine (1 1,12), barbiturates (13) and cocaine (14-16) on glucose metabolism have all been measured. In one particularly dramatic example, regional brain glucose metabolism in brain was found to parallel neurologic and immunologic improvement associated with azidothymidine treatment, demonstrating the ability of PET to provide a direct measure of drug response (11,12). OH
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PET has also been used to study the neurochemical effects of substances of abuse such as cocaine. Acut doses of cocaine (40 mg) had no effect on Dz receptor availability as measured by [1$C]N-methylspiroperidol (3)(17) whereas chronic cocaine produced a down-regulation of D2 receptors (18). Dopamine metabolism, as probed by 6-[18F]fluoro-L-DOPA (4) is also reduced in chronic cocaine abusers (16). These PET studies along with more classical methods strongly implicate the dopaminergic system in the reinforcing and addicting properties of cocaine (19).
PET studies of cocaine abusers have also revealed significant derangements in brain blood flow as measured by oxygen-15 water, an observation probably related to the drug's vasoactive properties which can lead to strokes and hemmorhage (20). Druq Bindinq Sites and Pharmacokinetics - PET has proven useful in identifying and characterizing drug binding sites, and in examining the relationship between the binding and kinetics of a drug and its behavioral effects in a quantitative manner. For example, the regional distribution and pharmacokinetics as well as the binding sites for cocaine have been determined using carbon-11 labeled cocaine in human and baboon brain (21). Cocaine is rapidly taken up and cleared from the striatum. Pretreatment with the dopamine reuptake inhibitor, nomifensine, significantly reduced binding in this region, thus implicating the dopamine reuptake site as the locus of cocaine's action. Moreover, the time course in the striatum parallels the temporal pattern of presentation of the "high" experienced after iv use of cocaine (22). In this case, the use of the labeled drug (cocaine) itself allows the neurochemical profile for binding and kinetics to be related to its behavioral action. PET permits, through a direct observation of drug binding, the evaluation of therapeutic interventions which could counteract the reinforcing properties of cocaine. The same strategies can be applied to other drugs of abuse.
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The binding sites f r haloperidol, the most widely used antipsychotic drug, have been determined using [ 8F]haloperidol (5) and PET (23). W ile it IS known that ' ' haloperidol binds to dopamine D2 receptors, the distribution of [1%Flhaloperidol in the brain is widespread and includes the cerebellum which is devoid of D2 receptors. Thus, other binding sites, such as the sigma receptor as well as non-receptor sites, may be partially responsible for the pharmacological profile of the drug (24).
Carbon-11 labeled cogentin (6) has been used to map the binding sites for this anticholinergic drug in human and baboon brain (25). Drug distribution in brain parallels the distribution of cholinergic receptors. Even though this drug is known to bind to the dopamine reuptake site, its binding is not altered by the dopamine reuptake inhibitor,
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nornifensine. Interactions betw en the cholinergic and th dopaminergic systems are currently being probed using lgF-N-methylspiroperidol ( l $F-NMS) and [' Clcogentin (26). In Vivo Radioreceptor Assay - Plasma drug levels are commonly taken as a measure of the amount of drug binding to target receptors. PET and radiotracers which selectively probe a particular neurotransmitter receptor can be used to examine this relationship directly. For example, the question of whether receptor occupancy by haloperidol parallels the concentr tion of drug in the plasm was addressed with PET using a serial study protocol with [13F]N-methylspiroperidol (B8F-NMS, 7 ) (using the ratio index as a measure of occupancy) (27). It was found that receptor occupancy increased with increasing plasma concentrations of the drug, leveling off at the 5-15 ng/ml, the initial phase of therapeutic levels for haloperidol. However, at higher plasma drug concentrations there was no further increase in receptor occupancy (28). This finding supports a growing clinical consensus that there is little added benefit in increasing pl srna haloperidol levels above 20 ng/cc. Similar results were obtained with [78 Br]bromospiperone (29). Serial PET studies have also been used to measure the clearance time of antipsychotic drugs from the D2 receptor (or the return of receptor availability to normal values by some other mechanism such as receptor synthesis). 02 receptor availability approaches norm I values after a 1 week drug free interval (27,28) However another PET study using [ 1QClraclopride (8) as the tracer showed a relatively constant, high receptor occupancy for many hours after the withdrawal of sulpiride or haloperidol (30).
-7 18F-NMS has been used to address the question of whether schizophrenic patients who respond to antipyschotic drugs have a higher receptor occupancy by drug than nonresponders (31). It was found that receptor blockade by haloperidol occurs to the same extent in responders and non-responders. Thus the treatment of nonresponders with high neuroleptic doses in order to increase receptor occupancy is not warranted.
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While the studies described above use PET to measure receptor availability, absolute receptor density (Bmax) has also been measured using this technology. Two different PET methods have been used to measure Bmax for D2 receptors in schizophrenia. An elevation in Bmax has been observed in post mortem brain tissue from individuals with schizophrenia, supporting the hypothesis that an overactivity of dopamine may play a role in this disease (32). When PET was used to measure Bmax in vivo, one group of investigators reported a significant elevation in Bmax (using [l 1C]]N-methylspiroperidol as a tracer) (33) and another group reported no deviation from normal values (using [l ICIraclopride) (34). The resolution of this apparent discrepancy is now being addressed by a detailed examination of the behavior of the tracers and the models used to calculate receptor density, as well as the patient population (35). One possible explanation for the results of the measurements with [ 11Clraclopride is that competition of intrasynaptic dopamine for the labeled raclopride may be significant since dopamine and raclopride have similar Kd's (36). The current controversy over what constitutes an accurate measurement of Bmax for the D2 receptor illustrates the complexities that can arise in PET work, but is also an example of where solutions can and will be found. Druq Interactions - The effects of drug combinations on the pharmacokinetics of a specific drug is a relevant question in drug research. For example, neuroleptic drugs are frequently given in combination with anticholinergic drugs to prevent or alleviate extrapyramidal symptoms. PET is now being used to examine the effects of anticholinergic drugs such as cogentin on the dopamine D2 receptor (26). Future work in this area may provide detailed information on the neurochemical consequences of drug interactions and offer scientific criteria for the use of drug combinations. Duration of Druq Action - The duration of action of drugs directly at their target sites has been measured with PET. L-Deprenyl is a monoamine oxidase B (MA0 B) selective suicide enzyme inactivator which has been shown to alter the natural history of Parkinson's disease (37). Carbon-I 1 labeled L-deprenyl (9) acts as a tracer for M A 0 B activity in the brain (38). The duration of M A 0 B inhibition after a single dose of Ldeprenyl has been measured in baboon brain over a 11 1 day time interval using 9 as a tracer (39). The recovery of the enzyme activity in vivo is remarkably slow with a half life of 30 days. Since (-)-deprenyl presumably acts by covalent attachment to M A 0 which results in the destruction of the enzyme, the recovery of M A 0 activity is related to the synthesis of enzyme.
-9 The duration of occupancy of mu-opiate receptors by naltrexone, an orally administered opiate antagonist has been measured using the mu-specific PET ligand, [l Clcarfentanil (1 0), and an external detector. The half-time of blockade by naltrexone in the brain ranged from 72 to 108 hours which corresponds to the half-time of the terminal plasma phase of naltrexone clearance (40). These studies, as well as the in vivo radioreceptor assays described above illustrate the power of in vivo imaging and detection, not only to probe the target sites for a drug, but also the duration of its pharmacological action. They may be of particular
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importance in the case of drugs which act by irreversibly inhibiting an enzyme or other biological substrate. Brain Uptake of Druas - A drug's ability to cross the blood-brain barrier, as well as its absolute uptake and time course are important properties which are difficult to determine -in vivo. However, PET is an excellent method for rapid measurement of brain uptake. PET studies of the stereoselectivity of cocaine binding provide a simple example (41). (-)-Cocaine is the behaviorally active natural product: behavioral research with (+)-cocaine showed low or no behavioral activity in monkeys (42). However, comparative PET studies with carbon-11 labeled (-)- and (+)-cocaine (11 and 12) showed that the (+)-enantiomer is not taken up in the brain, a very straightforward explanation of its behavioral impotency but one which had not been previously considered (42). Following this observation, it was shown that the (+)-enantiomer is metabolized in plasma so rapidly that there is essentially nothing available to cross the blood-brain-barrier (41). Thus biological activity of the (+)-enantiomer can only be assessed through direct administration assuming that brain metabolism of the compound is negligible.
The influence of factors such as diet on brain uptake of therapeutic drugs has al o been addressed with PET. The tracer for dopamine metabolism, 6[ 18FlfluoroDOPA, was used to determine whether dietary amino acids can interfere with brain uptake (and therapeutic actions) of L-DOPA in Parkinson's disease. The study concluded that a two to three-fold rise in plasma concentration of large neutral amino acids (phenylalanine, tyrosine, tryptophan, leucine, isoleucine, methionine, valine, and histidine) is sufficient to significantly compete with brain uptake of drug (43). Druq Delivery to Tarqet Tissue - PET has been used to directly compare intravenous versus intraarterial delivery of chemotherapeutic agents [carbon-11 labeled 1,3-bis-(2chloroethy1)-1-nitrosourea (13) and nitrogen-13 labeled cisplatin (14)] to malignant brain tumors (44,451). The drug delivery advantage of intraarterial chemotherapy was demonstrated and, in the case of 13, there are indications that this method may be of value in predicting clinical response. The accumulation of fluorine-18 labeled 5fluorouracil (15) in colorectal carcinoma was measured with PET in order to assess the effect of blood flow (as measured with 0-15 labeled water) on its delivery to tumor (46). This study demonstrated that PET can be used to identify patients with low 5-fluorouracil uptake who will probably not respond to standard chemotherapy with this agent. 0
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CLINICAL PET Clinical PET is just now beginning to emerge as a medical specialty. One can base a clinical PET program purely on Rb-82, I8FDG, the oxygen-15 labeled tracers, nitrogen-I 3 ammonia and fluorine-18 labeled fluoromethane (47,48). These materials are easily prepared with automated or robot controlled equipment and can be produced on demand. The many other labeled probes under study today will be synthesized and used routinely once their efficacy has been clearly demonstrated. PET research has its niche in the development of new probes for the study of basic problems in physiology, human biochemistry and medicine.
A number of unique clinical diagnostic applications have emerged from PET research. These include the identification of salvageable myocardium, the location of an epileptic focus for surgical removal and the differentiation of recurrent brain tumor from radiation necrosis (49-52). Coronarv Arterv Disease and Salvaqeable Myocardial Tissue - The patterns of metabolism in the human heart have proven to be powerful aids in the diagnosis of heart disease (53). PET can be used to identify patients with coronary artery disease with 95 % sensitivity. PET has much higher specificity and sensitivity than thallium imaging in determining coronary artery stenosis, myocardial ischemia and viability, and can minimize the need for invasive procedures such as coronary angiography (54). Myocardial perfusion is most commonly measured with generator produced rubidium-82 (half-life = 75 seconds), or cyclotron-produced nitrogen-I 3 ammonia, or oxygen-15 water. These tracers are used in a rest-stress serial study protocol. With sequential PET m ps of regional myocardial perfusion and regional myocardial glucose metabolism (with I l F D G ) , the viability of the myocardium can be determined. This information has been a v I able predictor of the outcome of coronary bypass surgery (55). More recently, [ elacetate has been used to provide an estimate of myocardial oxygen consumption; this method should facilitate the evaluation of therapeutic interventions designed to enhance the recovery of jeopardized myocardium (56). Newer probes for other aspects of myocardial metabolism have been described in Part I (1).
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EDilepsy - PET and I8FDG have been used successfully to locate the epileptic focus in patients whose seizures are inadequately controlled by medication and for whom surgery is anticipated (57-59). Since CT (x-ray computed tomography) and NMRl (nuclear magnetic resonance imaging) reveal no anatomical abnormalities in most of these patients, the location of the focus for surgery has required the placement of depth electrodes which in itself is accompanied by risks from the surgical procedure. laFDG images have been used to guide surgeons in the location and extent of the areas to be resected with very good preliminary results. In a recent report the accuracy of the location of an epileptic focus with PET was increased when [14C]carfen nil (10). a radiotracer specific for the mu opiate system, was used in conjunction with I8FDG (60). In the future, the use of (10) as well as other neurochemical probes such as ["GIRO 151788 (16) may be of value in identifying subpopulations of patients which may respond to specific drugs (61). Additionally, this specific neurochemical information may help limit the size of the resection.
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Brain Tumors - Newer tracers for probing specific aspects of tumor metabolism were described in Part I (1). To date, the major clinical application of PET has been in grading rain tumors and in differentiating recurrent tumor from treatment-related necrosi using ?8FDG as a tracer for glucose metabolism (62,63). However, the ability to relate Q8FDG uptake or metabolism to tumor grade has been recently questioned (64-66). There is also a recent report that the lumped constant (a constant which takes into account the different affinities of 2-deoxy-D-glucose and glucose for transport across the blood brain barrier and phosphorylation by hexokinase) in glioma differs significantly from that in normal brain tissue (67) in the rat. If this is also the case in human glioma, then calculation of the value of the tumor metabolic rate is directly affected. This is clearly a complex issue whose resolution could optimize the use of PET in the clinical management of cerebral malignancy. The value of PET in early detection and staging of different types of cancer is currently being investigated in a number of PET centers. Emerain0 Applications - Other applications with diagnostic potential are emerging. With PET, it is possible to directly correlate cognitive function, metabolism and structural integrity in the brain. In Alzheimer's Disease, PET has been used to identify characteristic deficits in brain metabolism which, in certain cases, have been shown to precede clinical presentation (68). In the future, when the metabolic abnormality is better characterized, PET may be used to differentiate normal aging from early Alzheimer's Disease. Also, PET can be useful in differentiating among the different types of dementias. Similarly, in neurodegenerative disorders such as Parkinson's disease, 6[' 8F]fluoro-L-DOPA (4).the previously mentioned probe for dopamine metabolism, is providing valuable new information (69). In Huntington's disease, PET complements clinical symptomology in establishing an early diagnosis (70). For example, a strong positive relationship was found between neuropsychological measures of verbal learning and memory and caudate metabolism, as measured by 18FDG (71). This was not found in the normal control group. PET has also been used to study psychiatric diseases such as schizophrenia, affective disorders, obsessive compulsive disorders, anxiety disorders, violence and substance abuse (72,73). Using PET and the 18FDG method, it now appears that bipolar and unipolar depression are two different disorders (73). Clinical research in psychiatry has been limited to the evaluation of brain pathology in difficult-to-diagnose patients. Although there still is no PET procedure of proven diagnostic or prognostic utility in psychiatric illness, this initial work is starting to identify abnormal patterns of brain metabolism and neurotransmitter activity associated with the different diseases. Future work in the characterization of the neurochemical and functional brain pathology of mental diseases could enhance the development of better therapeutic interventions. Other organs such as the lung are amenable to study with PET although the potential of this particular application is largely untapped. For example, pulmonary blood flow, ventilation, vascular permeability and metabolism are all measurable with PET and appropriate radiotracers (74). PET is coming of age and entering into routine clinical use. As we have described in this review, PET can be used to probe biochemistry and physiology noninvasively in humans and animals, in both normal and pathological states. It has virtually unexplored potential as an aid to drug design. PET will continue to stimulate basic research in multiple peripheral areas which bodes well for this exciting and growing field. References 1 J S Fowler and A P. Wolf Ann Rots Med Chem 74. . -. 277 - . - ... _ . (IqRq\ \.___ 2. M. Reivich, D. Kuhl. A. P. Wolf, J.&eenberg. M. PhTps, T. Ido, d..Casella, J. Fowler, E. Hoffrnann, A. Alavi, P. Som and L. Sokolotf. Circ. Res. 44 127 (1979). 3. M.M. TerPoaossian and P. Herscovitch. S F r . Nucl. Med.. XV. 377 119851 4 N D Volko< J D Brodie, A P Wolf, B Angrist, J Russell E d R Car&o: J Neurol , Neurosurg , Psych , 49,1199 (1986)
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47. K. Herholz. U. Pietrzyk. K. Wienhard, I. Hebold. G. Pawlik. R. Wagner, V. Holthoff, P. Klinkhammc.r, and W.-D. Heiss. Stroke, 20. 1174 (1989). 48. J.E. Holden, S.J. Gatley, R.D. Hichwa, W R. Ip, W.J. Shaughnessy, R.J. Nickles. and R.E. Polcyn. J. Nucl. Med. 22 1084(1981). 49. H.G. j&bsen, Ed.. JAMA 259 2438 1988 50. H.G. Jacobsen. Ed., JAMA: 260: 2704 I1988i: (1988). 51. H.G. Jacobsen, Ed., JAMA.=,2126 52. D.E. Kuhl. H.N. Wagner. Jr.. A. Alavi. R.E. Coleman, K.L. Gould, S.M. Larson. M.A. Mintun. B.A. Sieqel and P.K. Strudier. J. Nucl. Med., 2,1 136 (1988). 53. P. Camici. E. Ferrannini and L.H. OFlie, Prog. Cardiovasc. Dis., 32,217 (1989). 54. L. Gould. R. Goldstein and N. Mullani, J. Nucl. Med.. 30, 707, 1989. 55. J. Tillisch , R. Brunken. R. Marshall, M. Schwaiger, M.mandelkern, M. Phelps, and H. Scheibert, New Eng. H4, 884 (1 986). J. Med.. ; 56. M.N. Wal sh, E.M. Geltrnan. M.A. Brown, C.G. Henes. C.J. Weinheimer. B.E. Sobel arid S.R. Berqrnann. J. Nucl. M e d . , s , 1798 (1989). 57. D.E. Kuhl. J. Engel, Jr., M.E. Phelps andC. Selin. Ann. Neurol..B, 348 (1980). 58. R.F. Ochs, Y.L. Yamamoto, P. Gloor, J. T ler and W. Feindel. Neurology, 34(sup I 1). 125 (1984). Brooks, N. Patronas, R. De bFaz, DiChiro, R.M. Kessler. 59. W.H. Theodore, M.E. Newrnark, S. Sato, A. Margolin, and R. G. Manning, Ann. Neurol., 14.429 (1983). 60. J.J. Frost, H.S. Ma berg, R.S. Fisher, K.H. Douglas, R.F. Dannals. J.M. Links, A.A. Wilson, H.T. Ravert A.E. Rosenbaum. l . H . Snyder and H.N. Wa ner, Jr.. Ann. Neurol., 23,2313 (1988). 61. I. Savic, P. Roland, G. Sedvall. A. Persson, Pauli and L. Widen, Lancet 863 (1988). 62. G. DiChiro, Invest. Radiol. 22.360 (1986 63. N.J. Patronas. G. DiChir0,B.A. Brooks, L.L. DeLaPaz, P.L. Kornblith. B.H. Smith. H.V. Rizzoli. R.M. Kessler. R.G. Manning, M. Channing, A.P. Wolf and C.M. OConnor, Radiology, 144,885 (1982). 64. J.L. Tvler. M. Diksic. J.-G. Villemure. A.C. Evans..~E. Mever. , . Y.L. Yamamcto and W. Feindel. J. Nucl. Mid..'&!,' 1 123 (1987). 65. G. DiChiro and R.A. Brooks. J. Nucl. Med., 3, 421 (1988). 66. J.L. Tyler, M. Diksic. J.-G. Villemure, A.C. Evans, E. Meyer, Y.L. Yarn~motoand W. Feindel, J. Nucl. Med. 29 422 (1988). 37 67. R. KapGr, A.M. Spence. M. Muzi. M.M. Graham, G.L. Abbott and K.A. Krohn. J. Neurochem., 2.
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68. k.Ly&ady, J.V. Haxby, B. Horwitz, M. Sundaram, G. Ber MSchspiro, R.P. Friedland. and S.J. Rapoport. J. Clin. Experi. Neuropsychology. l o , 576 (198Ij. 69. W.R.W. Martin and M.R. Hayden, Can. J. Neurol. Sci. 14, 448 (1987). 70. J.C. Mazziotta. M.E. Phelps, J.J. Pahl, S.-C. Huang, L . F Eater. W.H. Riege, J.M. Hoffman, D.E. Kuhl. A.B. Lanto, J.A. Wapenski, andC.H. Markham, N. Eng. J. Med.. 316 (1987). 71. S. Berent. B. Giordani, S. Lehtinen, D. Markel, J.B. Penney, H. A. Buchtel. S.Starosta-Rubinstein. R. Hichwa and A.B. Young, Ann. Neurol:, 23, 541 (1988). 72. N.C. Andreasen. Science, 239. 1381 (1988). 73. J.M. Schwartz. L.R. Baxter. Jr.. J.C. Mazziotta. R.H. Gerner and M.E. Phelps, JAMA.258. 1368 (1987). 74. D.P. Schuster, Am. Rev. Respir. Dis., 139,818 (1989). 75. This chapter was prepared at Brookhaven National Laboratory under contract DE-AC02-76CH00016 with the U. S. Department of Energy and supported by its Ofice of Health and Environmental Research.
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PET has also been used to study the neurochemical effects of substances of abuse such as cocaine. Acut doses of cocaine (40 mg) had no effect on Dz receptor availability as measured by [1$C]N-methylspiroperidol (3)(17) whereas chronic cocaine produced a down-regulation of D2 receptors (18). Dopamine metabolism, as probed by 6-[18F]fluoro-L-DOPA (4) is also reduced in chronic cocaine abusers (16). These PET studies along with more classical methods strongly implicate the dopaminergic system in the reinforcing and addicting properties of cocaine (19).
PET studies of cocaine abusers have also revealed significant derangements in brain blood flow as measured by oxygen-15 water, an observation probably related to the drug's vasoactive properties which can lead to strokes and hemmorhage (20). Druq Bindinq Sites and Pharmacokinetics - PET has proven useful in identifying and characterizing drug binding sites, and in examining the relationship between the binding and kinetics of a drug and its behavioral effects in a quantitative manner. For example, the regional distribution and pharmacokinetics as well as the binding sites for cocaine have been determined using carbon-11 labeled cocaine in human and baboon brain (21). Cocaine is rapidly taken up and cleared from the striatum. Pretreatment with the dopamine reuptake inhibitor, nomifensine, significantly reduced binding in this region, thus implicating the dopamine reuptake site as the locus of cocaine's action. Moreover, the time course in the striatum parallels the temporal pattern of presentation of the "high" experienced after iv use of cocaine (22). In this case, the use of the labeled drug (cocaine) itself allows the neurochemical profile for binding and kinetics to be related to its behavioral action. PET permits, through a direct observation of drug binding, the evaluation of therapeutic interventions which could counteract the reinforcing properties of cocaine. The same strategies can be applied to other drugs of abuse.
P
The binding sites f r haloperidol, the most widely used antipsychotic drug, have been determined using [ 8F]haloperidol (5) and PET (23). W ile it IS known that ' ' haloperidol binds to dopamine D2 receptors, the distribution of [1%Flhaloperidol in the brain is widespread and includes the cerebellum which is devoid of D2 receptors. Thus, other binding sites, such as the sigma receptor as well as non-receptor sites, may be partially responsible for the pharmacological profile of the drug (24).
Carbon-11 labeled cogentin (6) has been used to map the binding sites for this anticholinergic drug in human and baboon brain (25). Drug distribution in brain parallels the distribution of cholinergic receptors. Even though this drug is known to bind to the dopamine reuptake site, its binding is not altered by the dopamine reuptake inhibitor,
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nornifensine. Interactions betw en the cholinergic and th dopaminergic systems are currently being probed using lgF-N-methylspiroperidol ( l $F-NMS) and [' Clcogentin (26). In Vivo Radioreceptor Assay - Plasma drug levels are commonly taken as a measure of the amount of drug binding to target receptors. PET and radiotracers which selectively probe a particular neurotransmitter receptor can be used to examine this relationship directly. For example, the question of whether receptor occupancy by haloperidol parallels the concentr tion of drug in the plasm was addressed with PET using a serial study protocol with [13F]N-methylspiroperidol (B8F-NMS, 7 ) (using the ratio index as a measure of occupancy) (27). It was found that receptor occupancy increased with increasing plasma concentrations of the drug, leveling off at the 5-15 ng/ml, the initial phase of therapeutic levels for haloperidol. However, at higher plasma drug concentrations there was no further increase in receptor occupancy (28). This finding supports a growing clinical consensus that there is little added benefit in increasing pl srna haloperidol levels above 20 ng/cc. Similar results were obtained with [78 Br]bromospiperone (29). Serial PET studies have also been used to measure the clearance time of antipsychotic drugs from the D2 receptor (or the return of receptor availability to normal values by some other mechanism such as receptor synthesis). 02 receptor availability approaches norm I values after a 1 week drug free interval (27,28) However another PET study using [ 1QClraclopride (8) as the tracer showed a relatively constant, high receptor occupancy for many hours after the withdrawal of sulpiride or haloperidol (30).
-7 18F-NMS has been used to address the question of whether schizophrenic patients who respond to antipyschotic drugs have a higher receptor occupancy by drug than nonresponders (31). It was found that receptor blockade by haloperidol occurs to the same extent in responders and non-responders. Thus the treatment of nonresponders with high neuroleptic doses in order to increase receptor occupancy is not warranted.
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While the studies described above use PET to measure receptor availability, absolute receptor density (Bmax) has also been measured using this technology. Two different PET methods have been used to measure Bmax for D2 receptors in schizophrenia. An elevation in Bmax has been observed in post mortem brain tissue from individuals with schizophrenia, supporting the hypothesis that an overactivity of dopamine may play a role in this disease (32). When PET was used to measure Bmax in vivo, one group of investigators reported a significant elevation in Bmax (using [l 1C]]N-methylspiroperidol as a tracer) (33) and another group reported no deviation from normal values (using [l ICIraclopride) (34). The resolution of this apparent discrepancy is now being addressed by a detailed examination of the behavior of the tracers and the models used to calculate receptor density, as well as the patient population (35). One possible explanation for the results of the measurements with [ 11Clraclopride is that competition of intrasynaptic dopamine for the labeled raclopride may be significant since dopamine and raclopride have similar Kd's (36). The current controversy over what constitutes an accurate measurement of Bmax for the D2 receptor illustrates the complexities that can arise in PET work, but is also an example of where solutions can and will be found. Druq Interactions - The effects of drug combinations on the pharmacokinetics of a specific drug is a relevant question in drug research. For example, neuroleptic drugs are frequently given in combination with anticholinergic drugs to prevent or alleviate extrapyramidal symptoms. PET is now being used to examine the effects of anticholinergic drugs such as cogentin on the dopamine D2 receptor (26). Future work in this area may provide detailed information on the neurochemical consequences of drug interactions and offer scientific criteria for the use of drug combinations. Duration of Druq Action - The duration of action of drugs directly at their target sites has been measured with PET. L-Deprenyl is a monoamine oxidase B (MA0 B) selective suicide enzyme inactivator which has been shown to alter the natural history of Parkinson's disease (37). Carbon-I 1 labeled L-deprenyl (9) acts as a tracer for M A 0 B activity in the brain (38). The duration of M A 0 B inhibition after a single dose of Ldeprenyl has been measured in baboon brain over a 11 1 day time interval using 9 as a tracer (39). The recovery of the enzyme activity in vivo is remarkably slow with a half life of 30 days. Since (-)-deprenyl presumably acts by covalent attachment to M A 0 which results in the destruction of the enzyme, the recovery of M A 0 activity is related to the synthesis of enzyme.
-9 The duration of occupancy of mu-opiate receptors by naltrexone, an orally administered opiate antagonist has been measured using the mu-specific PET ligand, [l Clcarfentanil (1 0), and an external detector. The half-time of blockade by naltrexone in the brain ranged from 72 to 108 hours which corresponds to the half-time of the terminal plasma phase of naltrexone clearance (40). These studies, as well as the in vivo radioreceptor assays described above illustrate the power of in vivo imaging and detection, not only to probe the target sites for a drug, but also the duration of its pharmacological action. They may be of particular
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importance in the case of drugs which act by irreversibly inhibiting an enzyme or other biological substrate. Brain Uptake of Druas - A drug's ability to cross the blood-brain barrier, as well as its absolute uptake and time course are important properties which are difficult to determine -in vivo. However, PET is an excellent method for rapid measurement of brain uptake. PET studies of the stereoselectivity of cocaine binding provide a simple example (41). (-)-Cocaine is the behaviorally active natural product: behavioral research with (+)-cocaine showed low or no behavioral activity in monkeys (42). However, comparative PET studies with carbon-11 labeled (-)- and (+)-cocaine (11 and 12) showed that the (+)-enantiomer is not taken up in the brain, a very straightforward explanation of its behavioral impotency but one which had not been previously considered (42). Following this observation, it was shown that the (+)-enantiomer is metabolized in plasma so rapidly that there is essentially nothing available to cross the blood-brain-barrier (41). Thus biological activity of the (+)-enantiomer can only be assessed through direct administration assuming that brain metabolism of the compound is negligible.
The influence of factors such as diet on brain uptake of therapeutic drugs has al o been addressed with PET. The tracer for dopamine metabolism, 6[ 18FlfluoroDOPA, was used to determine whether dietary amino acids can interfere with brain uptake (and therapeutic actions) of L-DOPA in Parkinson's disease. The study concluded that a two to three-fold rise in plasma concentration of large neutral amino acids (phenylalanine, tyrosine, tryptophan, leucine, isoleucine, methionine, valine, and histidine) is sufficient to significantly compete with brain uptake of drug (43). Druq Delivery to Tarqet Tissue - PET has been used to directly compare intravenous versus intraarterial delivery of chemotherapeutic agents [carbon-11 labeled 1,3-bis-(2chloroethy1)-1-nitrosourea (13) and nitrogen-13 labeled cisplatin (14)] to malignant brain tumors (44,451). The drug delivery advantage of intraarterial chemotherapy was demonstrated and, in the case of 13, there are indications that this method may be of value in predicting clinical response. The accumulation of fluorine-18 labeled 5fluorouracil (15) in colorectal carcinoma was measured with PET in order to assess the effect of blood flow (as measured with 0-15 labeled water) on its delivery to tumor (46). This study demonstrated that PET can be used to identify patients with low 5-fluorouracil uptake who will probably not respond to standard chemotherapy with this agent. 0
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CLINICAL PET Clinical PET is just now beginning to emerge as a medical specialty. One can base a clinical PET program purely on Rb-82, I8FDG, the oxygen-15 labeled tracers, nitrogen-I 3 ammonia and fluorine-18 labeled fluoromethane (47,48). These materials are easily prepared with automated or robot controlled equipment and can be produced on demand. The many other labeled probes under study today will be synthesized and used routinely once their efficacy has been clearly demonstrated. PET research has its niche in the development of new probes for the study of basic problems in physiology, human biochemistry and medicine.
A number of unique clinical diagnostic applications have emerged from PET research. These include the identification of salvageable myocardium, the location of an epileptic focus for surgical removal and the differentiation of recurrent brain tumor from radiation necrosis (49-52). Coronarv Arterv Disease and Salvaqeable Myocardial Tissue - The patterns of metabolism in the human heart have proven to be powerful aids in the diagnosis of heart disease (53). PET can be used to identify patients with coronary artery disease with 95 % sensitivity. PET has much higher specificity and sensitivity than thallium imaging in determining coronary artery stenosis, myocardial ischemia and viability, and can minimize the need for invasive procedures such as coronary angiography (54). Myocardial perfusion is most commonly measured with generator produced rubidium-82 (half-life = 75 seconds), or cyclotron-produced nitrogen-I 3 ammonia, or oxygen-15 water. These tracers are used in a rest-stress serial study protocol. With sequential PET m ps of regional myocardial perfusion and regional myocardial glucose metabolism (with I l F D G ) , the viability of the myocardium can be determined. This information has been a v I able predictor of the outcome of coronary bypass surgery (55). More recently, [ elacetate has been used to provide an estimate of myocardial oxygen consumption; this method should facilitate the evaluation of therapeutic interventions designed to enhance the recovery of jeopardized myocardium (56). Newer probes for other aspects of myocardial metabolism have been described in Part I (1).
v
EDilepsy - PET and I8FDG have been used successfully to locate the epileptic focus in patients whose seizures are inadequately controlled by medication and for whom surgery is anticipated (57-59). Since CT (x-ray computed tomography) and NMRl (nuclear magnetic resonance imaging) reveal no anatomical abnormalities in most of these patients, the location of the focus for surgery has required the placement of depth electrodes which in itself is accompanied by risks from the surgical procedure. laFDG images have been used to guide surgeons in the location and extent of the areas to be resected with very good preliminary results. In a recent report the accuracy of the location of an epileptic focus with PET was increased when [14C]carfen nil (10). a radiotracer specific for the mu opiate system, was used in conjunction with I8FDG (60). In the future, the use of (10) as well as other neurochemical probes such as ["GIRO 151788 (16) may be of value in identifying subpopulations of patients which may respond to specific drugs (61). Additionally, this specific neurochemical information may help limit the size of the resection.
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Brain Tumors - Newer tracers for probing specific aspects of tumor metabolism were described in Part I (1). To date, the major clinical application of PET has been in grading rain tumors and in differentiating recurrent tumor from treatment-related necrosi using ?8FDG as a tracer for glucose metabolism (62,63). However, the ability to relate Q8FDG uptake or metabolism to tumor grade has been recently questioned (64-66). There is also a recent report that the lumped constant (a constant which takes into account the different affinities of 2-deoxy-D-glucose and glucose for transport across the blood brain barrier and phosphorylation by hexokinase) in glioma differs significantly from that in normal brain tissue (67) in the rat. If this is also the case in human glioma, then calculation of the value of the tumor metabolic rate is directly affected. This is clearly a complex issue whose resolution could optimize the use of PET in the clinical management of cerebral malignancy. The value of PET in early detection and staging of different types of cancer is currently being investigated in a number of PET centers. Emerain0 Applications - Other applications with diagnostic potential are emerging. With PET, it is possible to directly correlate cognitive function, metabolism and structural integrity in the brain. In Alzheimer's Disease, PET has been used to identify characteristic deficits in brain metabolism which, in certain cases, have been shown to precede clinical presentation (68). In the future, when the metabolic abnormality is better characterized, PET may be used to differentiate normal aging from early Alzheimer's Disease. Also, PET can be useful in differentiating among the different types of dementias. Similarly, in neurodegenerative disorders such as Parkinson's disease, 6[' 8F]fluoro-L-DOPA (4).the previously mentioned probe for dopamine metabolism, is providing valuable new information (69). In Huntington's disease, PET complements clinical symptomology in establishing an early diagnosis (70). For example, a strong positive relationship was found between neuropsychological measures of verbal learning and memory and caudate metabolism, as measured by 18FDG (71). This was not found in the normal control group. PET has also been used to study psychiatric diseases such as schizophrenia, affective disorders, obsessive compulsive disorders, anxiety disorders, violence and substance abuse (72,73). Using PET and the 18FDG method, it now appears that bipolar and unipolar depression are two different disorders (73). Clinical research in psychiatry has been limited to the evaluation of brain pathology in difficult-to-diagnose patients. Although there still is no PET procedure of proven diagnostic or prognostic utility in psychiatric illness, this initial work is starting to identify abnormal patterns of brain metabolism and neurotransmitter activity associated with the different diseases. Future work in the characterization of the neurochemical and functional brain pathology of mental diseases could enhance the development of better therapeutic interventions. Other organs such as the lung are amenable to study with PET although the potential of this particular application is largely untapped. For example, pulmonary blood flow, ventilation, vascular permeability and metabolism are all measurable with PET and appropriate radiotracers (74). PET is coming of age and entering into routine clinical use. As we have described in this review, PET can be used to probe biochemistry and physiology noninvasively in humans and animals, in both normal and pathological states. It has virtually unexplored potential as an aid to drug design. PET will continue to stimulate basic research in multiple peripheral areas which bodes well for this exciting and growing field. References 1 J S Fowler and A P. Wolf Ann Rots Med Chem 74. . -. 277 - . - ... _ . (IqRq\ \.___ 2. M. Reivich, D. Kuhl. A. P. Wolf, J.&eenberg. M. PhTps, T. Ido, d..Casella, J. Fowler, E. Hoffrnann, A. Alavi, P. Som and L. Sokolotf. Circ. Res. 44 127 (1979). 3. M.M. TerPoaossian and P. Herscovitch. S F r . Nucl. Med.. XV. 377 119851 4 N D Volko< J D Brodie, A P Wolf, B Angrist, J Russell E d R Car&o: J Neurol , Neurosurg , Psych , 49,1199 (1986)
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