Seminars in Nuclear Medicine
Volume 33, Issue 1 , Pages 14-27 , January 2003

Radiotracers for positron emission tomography imaging

References 

  1. Fowler JS, Wolf AP. Positron emitter-labeled compounds: Priorities and problems. In: Phelps M, Mazziotta J, Schelbert H editor. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart, chapter 9. New York, NY: Raven Press; 1986;p. 391–450
  2. Kilbourn MR. Fluorine-18 Labeling of Radiopharmaceuticals. In: Nuclear Science Series No. NAS-NS-3203. Washington, DC: National Academy Press; 1990;
  3. Tewson TJ, Krohn KA. PET radiopharmaceuticals: State-of-the-art and future prospects. In: Semin Nucl Med. 28:1998;p. 221–234
  4. Fowler JS, Wolf AP. Working against time. Rapid radiotracer synthesis and imaging the human brain. Accts Chem Res. 1997;30:181–188
  5. Reference book for PET radiopharmaceuticals. Available at: Iwata R.
  6. Langstrom B, Kihlberg T, Bergstrom M, et al. Compounds labelled with short-lived beta(+)-emitting radionuclides and some applications in life sciences. The importance of time as a parameter. Acta Chem Scand. 1999;53:651–669
  7. Brodack J, Kilbourn M, Welch M. Automated production of several positron-emitting radiopharmaceuticals using a single laboratory robot. Appl Radiat Isot. 1988;39:689–698
  8. Satyamurthy N, Phelps ME, Barrio JR. Electronic generators for the production of positron-emitter labeled radiopharmaceuticals: Where would PET be without them?. Clin Positron Imaging. 1999;2:233–252
  9. Alexoff DL. Knowledge-based automated radiopharmaceutical manufacturing for positron emission tomography. In: Emran AN editors. New Trends in Radiopharmaceutical Synthesis. New York, NY: Plenum Press; 1991;p. 339–353
  10. Vera-Ruiz H, Marcus CS, Pike VW, et al. Report of an International Atomic Energy Agency's Advisory Group meeting on “Quality control of cyclotron-produced radiopharmaceuticals”. In: Int J Rad Appl Instrum B. 17:1990;p. 445–456
  11. Deutsch A, Roth RH. Neurochemical systems in the central nervous system. In: Charney DS, Nestler EJ, Bunney BS editor. Neurobiology of Mental Illness. New York, NY: Oxford University Press; 1999;p. 10–25
  12. Volkow ND, Fowler JS, Gatley SJ, et al. PET evaluation of the dopamine system of the human brain. J Nucl Med. 1996;37:1242–1256
  13. Garnett ES, Firnau G, Nahmias C. Dopamine visualized in the basal ganglia in living man. Nature. 1983;305:137–138
  14. Firnau G, Garnett ES, Chirakal R, et al. [18F]Fluoro-l-dopa for the in vivo study of intracerebral dopamine. Int J Rad Appl Instrum A. 1986;37:669–675
  15. Firnau G, Sood S, Chirakal R, et al. Cerebral metabolism of 6-18F-fluoro-l-3,4-dihydroxy-phenylalanine in the primate. J Neurochem. 1987;48:1077–1082
  16. Perlmutter JS. New insights into a pathophysiology of Parkinson's disease: The challenge of positron emission tomography. Trends Neurosci. 1988;11:203–208
  17. DeJesus OT, Endres CJ, Shelton SE, et al. Evaluation of fluorinated m-tyrosine analogs as PET imaging agents of dopamine nerve terminals: Comparison with 6-fluoroDOPA. J Nucl Med. 1997;38:630–636
  18. Bjurling P, Antoni G, Watanabe Y, et al. Enzymatic synthesis of carboxy-11C-labeled l-tyrosine, l-DOPA, l-tryptophan and 5-hydroxy-l-tryptophan. Acta Chem Scand. 1990;44:178–182
  19. Farde L, Wiesel F-A, Halldin C, et al. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45:71–76
  20. Satyamurthy N, Barrio JR, Bida G, et al. 3-(2′-[18F]Fluoroethyl)spiperone, a potent dopamine antagonist: Synthesis, structural analysis and in-vivo utilization in humans. Appl Radiat Isot. 1990;41:113–129
  21. Welch MJ, Katzenellenbogen JA, Mathias CJ, et al. N-(3-[18F]fluoropropyl)-Spiperone: The preferred 18F labeled spiperone analog for PET studies of the dopamine receptor. Nucl Med Biol. 1998;15:83–97
  22. Gambhir SS, Barrio JR, Herschman HR, et al. Assays for noninvasive imaging of reporter gene expression. Nucl Med Biol. 1999;26:481–490
  23. Logan J, Dewey SL, Wolf AP, et al. Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: Comparison of simulations and experimental results from PET studies in baboons. Synapse. 1991;9:195–207
  24. Farde L, Ehrin E, Eriksson L, et al. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. In: Proc Natl Acad Sci USA. 82:1985;p. 3863–3867
  25. Moerlein S, Perlmutter JS, Welch MJ. USP standards for raclopride C 11 injection. Pharmacopeial Forum. 1995;21:172–176
  26. Dewey SL, Smith GS, Logan J, et al. Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse. 1993;13:350–356
  27. Volkow ND, Wang G-J, Fowler JS, et al. Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse. 1994;16:255–262
  28. Volkow ND, Wang G-J, Fowler JS, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386:830–833
  29. Breier A, Su TP, Saunders R, et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. In: Proc Natl Acad Sci USA. 94:1997;p. 2569–2574
  30. Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review. J Cereb Blood Flow Metab. 2000;20:423–451
  31. de la Fuente-Fernandez R, Ruth TJ, Sossi V. Expectation and dopamine release: Mechanism of the placebo effect in Parkinson's disease. Science. 2001;293:1164–1166
  32. Mathis CA, Bishop JE, Gerdes JM, et al. Synthesis and evaluation of high affinity aryl substituted [18F]fluoropropylbenzamides for dopamine D2 receptor studies. Nucl Med Biol. 1992;19:571–588
  33. Mach RH, Nader MA, Ehrenkaufer RLE, et al. Comparison of two fluorine-18 labeled benzamide derivatives that bind reversibly to dopamine D2 receptors: In vitro binding studies and positron emission tomography. Synapse. 1996;24:322–333
  34. Christian BT, Narayanan TK, Shi B, et al. Quantitation of striatal and extrastriatal D-2 dopamine receptors using PET imaging of [18F]fallypride in nonhuman primates. Synapse. 2000;38:71–79
  35. Kessler RM, Votaw JR, dePaulis T, et al. Evaluation of 5-[18F]fluoropropylepidepride as a potential PET radioligand for imaging dopamine D2 receptors. Synapse. 1993;15:169–176
  36. Halldin C, Farde L, Hogberg T, et al. Carbon-11-FLB 457: A radioligand for extrastriatal D2 dopamine receptors. J Nucl Med. 1995;36:1275–1281
  37. Chou YH, Halldin C, Farde L. Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: A PET study. Synapse. 2000;38:138–143
  38. Halldin CJ, Swahn C-G, Neumeyer JL, et al. Preparation of two potent and selective dopamine D2 receptor agonists: R-[propyl-11C]-2-OHNPA and R-[methyl-11C]-2-OCH3-NPA. J Label Compound Radiopharm. 1993;32:S265–S266
  39. Zilstra S. Synthesis and in vivo distribution in the rat of several fluorine-18 labeled N-fluoroalkylaporphines. Appl Radiat Isot. 1993;44:651–658
  40. Shi B, Narayanan TK, Yang ZY. Radiosynthesis and in vitro evaluation of 2-(N-alkyl-N-1-11C-propyl)amino-5-hydroxytetralin analogs as high affinity agonists for dopamine D2 receptors. Nucl Med Biol. 1999;26:725–735
  41. Hwang D-R, Kegeles LS, Laruelle M. (−)-N-[11C]Propyl-norapomorphine: A positron-labeled dopamine agonist for PET imaging of D2 receptors. Nucl Med Biol. 2000;27:533–539
  42. Halldin C, Foged C, Chou Y-H, et al. Carbon-11-NNC 112: A radioligand for PET examination of striatal and neocortical D1-dopamine receptors. J Nucl Med. 1998;39:2061–2068
  43. Abi-Dargham A, Martinez D, Mawlawi O, et al. Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: Validation and reproducibility. J Cereb Blood Flow Metab. 2000;20:225–243
  44. DaSilva JN, Wilson AA, Nobrega JN, et al. Synthesis and autoradiographic localization of the dopamine D-1 agonists [11C]SKF 75670 and [11]SKF 82957 as potential PET radioligands. Appl Radiat Isot. 1996;47:279–284
  45. Abi-Dargham A, Simpson N, Kegeles L, et al. PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756. Synapse. 1999;32:93–109
  46. Chou YH, Karlsson P, Halldin C, et al. A PET study of D1 like dopamine receptor ligand binding during altered endogenous dopamine levels in the primate brain. Psychopharmacology. 1999;146:220–227
  47. Langer O, Halldin C, Chou Y-H, et al. Carbon-11 PB-12: An attempt to visualize the dopamine D4 receptor in the primate brain with positron emission tomography. Nucl Med Biol. 2000;27:707–714
  48. Joyce JN. Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs. Pharmacol Ther. 2001;90:231–259
  49. Fowler JS, Volkow ND, Wang G-J, et al. [11C]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy. Nucl Med Biol. 2001;28:561–572
  50. Volkow ND, Fowler JS, Wang G-J, et al. Decreased dopamine transporters with age in healthy human subjects. Ann Neurol. 1994;36:237–239
  51. Tedroff J, Aquilonius S-M, Hartvig P, et al. Monoamine reuptake sites in the human brain evaluated in vivo by means of 11C nomifensine and positron emission tomography: The effect of age and Parkinson's disease. Acta Neurol Scand. 1988;77:92–101
  52. Volkow ND, Wang G-J, Fischman M, et al. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature. 1997;386:827–830
  53. Volkow ND, Wang G-J, Fowler JS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry. 1998;155:1325–1331
  54. Logan J, Fowler JS, Volkow ND, et al. Graphical analysis of reversible radioligand binding from time activity measurements applied to [N-11C-methyl]-(−)cocaine PET studies in human subjects. J Cereb Blood Flow Metab. 1990;10:740–747
  55. Kilbourn MR. In vivo tracers for vesicular neurotransmitter transporters. Nucl Med Biol. 1997;24:615–619
  56. Frey KA, Koeppe RA, Kilbourn MR, et al. Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging. Ann Neurol. 1996;40:873–884
  57. Singer T. Monoamine oxidases: Old friends hold many surprises. FASEB J. 1995;9:605–610
  58. Fowler JS, MacGregor RR, Wolf AP, et al. Mapping human brain monoamine oxidase A and B with 11C-suicide inactivators and positron emission tomography. Science. 1987;235:481–485
  59. Fowler JS, Wang G-J, Logan J, et al. Selective reduction of radiotracer trapping by deuterium substitution: Comparison of [11C]l-deprenyl and [11C]l-deprenyl-D2 for MAO B mapping. J Nucl Med. 1995;36:1255–1262
  60. Fowler JS, Volkow ND, Wang G-J, et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature. 1996;379:733–736
  61. Fowler JS, Volkow ND, Wang G-J, et al. Brain monoamine oxidase A inhibition in cigarette smokers. In: Proc Natl Acad Sci USA. 93:1996;p. 14065–14069
  62. Khalil AA, Steyn S, Castagnoli N. Isolation and characterization of a monoamine oxidase inhibitor from tobacco leaves. Chem Res Toxicol. 2000;13:31–35
  63. Rose JE, Behm FM, Ramsey C, et al. Platelet monoamine oxidase, smoking cessation, and tobacco withdrawal symptoms. Nicotine Tob Res. 2001;3:383–390
  64. Morens DM, Grandinetti A, Reed D, et al. Cigarette smoking and protection from Parkinson's disease: False association or etiologic clue?. Neurology. 1995;45:1041–1051
  65. Bergstrom M, Westerberg G, Kihberg T, et al. Synthesis of some 11C-labeled MAO A inhibitors and their in vivo uptake kinetics. Nucl Med Biol. 1997;24:381–388
  66. Bernard S, Fuseau C, Schmid L, et al. Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor 5-[4-benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazo-[11C]-2(3H)-one. Eur J Nucl Med. 1996;23:150–156
  67. Dolle F, Bramoulle Y, Bottlaender M, et al. [11C]Befloxatone, a novel highly potent radioligand for in vivo imaging of monoamine oxidase A. J Label Compound Radiopharm. 1999;42(suppl 1):S608–S609
  68. Lavigne JA, Helzlsouer KJ, Huang H-Y, et al. An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res. 1997;57:5493–5497
  69. Ding Y-S, Gatley SJ, Fowler JS, et al. Mapping catechol-O-methyltransferase in vivo: Initial studies with [18F]Ro41-0960. Life Sci. 1996;58:195–208
  70. Ding Y-S, Logan J, Gatley SJ, et al. PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960. J Neural Transm. 1998;105:1199–2111
  71. 100P Ding YS, Pyatt B, Fowler JS, et al. A potential use of [18F]Ro41-0960, a selective COMT inhibitor, for PET imaging of estrogen metabolism in breast cancer. (abstr) J Nucl Med. 1999;40:
  72. Crouzel C, Guillaume M, Barre L, et al. Ligands and tracers for PET studies of the 5-HT system—Current status. Nucl Med Biol. 1992;19:857–870
  73. Pike VW. Radioligands for PET studies of central 5-HT receptors and re-uptake sites—Current status. Nucl Med Biol. 1995;22:1011–1018
  74. In: Proceedings of the Conference on the imaging of brain 5-HT1A receptors in vivo-Radioligands, clinical application and drug development. Nucl Med Biol. 27:2000;(special issue) 5
  75. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–1152
  76. Wong DF, Wagner HN, Dannals RF, et al. Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science. 1984;226:1393–1396
  77. Wang G-J, Volkow ND, Logan J, et al. Evaluation of age-related changes in serotonin 5-HT2 and dopamine D2 receptor availability in healthy human subjects. Life Sci. 1995;56:249–253
  78. Biver F, Goldman S, Luxen A, et al. Multicompartmental study of fluorine-18 altanserin binding to brain 5-HT2 receptors in humans using positron emission tomography. Eur J Nucl Med. 1994;21:937–946
  79. Blin J, Sette G, Fiorelli M, et al. A method for the in vivo investigation of the serotonergic 5-HT2 receptors in the human cerebral cortex using positron emission tomography and 18F-labeled setoperone. J Neurochem. 1990;54:1744–1754
  80. Ito H, Nyberg S, Halldin C, et al. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J Nucl Med. 1998;39:208–214
  81. Mathis CA, Mahmood K, Simpson NR, et al. Synthesis and preliminary in vivo evaluation of [11C]MDL 100907: A potent and selective radioligand for the 5-HT2A receptor system. Med Chem Res. 1996;6:1–10
  82. Van Dyck CH, Tan PZ, Baldwin RM, et al. PET quantification of 5-HT2A receptors in the human brain: A constant infusion paradigm with [18F]altanserin. J Nucl Med. 2000;41:234–241
  83. Mathis CA, Simpson NR, Mahmood K, et al. [11C]WAY 100635: A radiologand for imaging 5-HT1A receptors with positron emission tomography. Life Sci. 1994;55:PL403–PL407
  84. Farde L, Ito H, Swahn C-G, et al. Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytrypamine-1A receptors in man. J Nucl Med. 1998;39:1965–1971
  85. Farde L, Ito H, Swahn C-G, et al. Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med. 1998;39:1965–1971
  86. Shiue C-Y, Shiue GG, Mozley PD, et al. P-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans. Synapse. 1997;25:147–154
  87. Plenevaux A, Lemaire C, Aerts J, et al. [18F]p-MPPF: A radiolabeled antagonist for the study of 5HT1A receptors with PET. Nucl Med Biol. 2000;27:467–471
  88. Plenevaux A, Weissmann D, Aerts J, et al. Tissue distribution, autoradiography, and metabolism of 4-(2′-methoxyphenyl)-1-[2′-[N-2′-pyridinyl)-p-[(18)F]fluorobenzamido-ethyl] piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist for positron emission tomography: An in vivo study in rats. J Neurochem. 2000;75:803–811
  89. Suehiro M, Ravert HT, Dannals RF, et al. Synthesis of a radiotracer for studying serotonin uptake sites with positron emission tomography: [11C]McN-5652-Z. J Label Compound Radiopharm. 1992;31:841–848
  90. Szabo Z, Kao PF, Scheffel U, et al. Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652. Synpse. 1995;20:37–43
  91. Suehiro M, Scheffel U, Ravert HT, et al. [11C](+)McN5652 as a radiotracer for imaging serotonin uptake sites with PET. Life Sci. 1993;53:883–892
  92. Buck A, Guiker PM, Schönbächler RD, et al. Evaluation of serotonergic transporters using PET and [11C](+)McN-5652: Assessment of methods. J Cereb Blood Flow Metab. 2000;20:253–262
  93. Houle S, Ginovart N, Hussey D, et al. Imaging the serotonin transporter with positron emission tomography: Initial human studies with [11C]DAPP and [11C]DASB. Eur J Nucl Med. 2000;11:1719–1722
  94. Scheffel U, Dannals RF, Suehiro M, et al. Evaluation of 11C-citalopram and 11C-fluoxetine as in vivo ligands for the serotonin uptake site. J Nucl Med. 1990;31:883–884
  95. Dannals RF, Ravert HT, Wilson AA, et al. Synthesis of a radiotracer for studying serotonin-2 receptors: Carbon-11 labelled N-methylparoxetine. J Label Compound Radiopharm. 1989;26:205–206
  96. Kilbourn MR, Haka MS, Mulholland GK, et al. Synthesis of radiolabeled inhibitors or presynaptic monoamine uptake systems: [18F]GBR 13119 (DA), [11C]nisoxetine (NE), and [11C]fluoxetine (5-HT). J Label Compound Radiopharm. 1989;26:412–414
  97. Diksic M, Tohyama Y, Takada A. Brain net unidirectional uptake of α-methyltryptophan. Neurochem Res. 2000;25:1537–1546
  98. Diksic M, Nagahiro S, Sources TL, et al. A new method to measure brain serotonin synthesis in vivo. Theory and basis data for a biological model. J Cereb Blood Flow Metab. 1990;10:1–12
  99. Shoaf SE, Carson RE, Hommer D, et al. The suitability of [11C]-(-methy-l-tryptophan as a tracer for serotonin synthesis: Studies with dual administration of [11C] and [14C] labeled tracer. J Cereb Blood Flow Metab. 2000;20:244–252
  100. Frost JJ. PET imaging of the opioid receptor: The early years. Nucl Med Biol. 2001;28:509–513
  101. Dannals RF, Ravert HT, Frost JJ, et al. Radiosynthesis of an opiate receptor binding radiotracer: [11C]Carfentanil. Int J Appl Radiat Isot. 1985;36:303–306
  102. Frost JJ, Wagner HN, Dannals RF, et al. Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomogr. 1985;9:231–236
  103. Zubieta JK, Dannals RF, Frost JJ. Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry. 1999;156:842–848
  104. Zubieta JK, Smith YR, Bueller JA, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311–315
  105. Luthra AK, Pike VW, Brady F. The preparation of carbon-11 labelled diprenorphine: A new radioligand for the study of the opiate receptor system in vivo. J Chem Soc Chem Commun. 1985;1423–1425
  106. Luthra SK, Pike VW, Brady F, et al. Preparation of [11C]buprenorphine—A potential radioligand for the study of opiate receptor system in vivo. Appl Radiat Isot. 1987;38:65–66
  107. Lever JR, Mazza SM, Dannals RF, et al. Facile synthesis of [11C]buprenorphine for positron emission tomographic studies. Appl Radiat Isot. 1990;41:745–752
  108. Galynker I, Schlyer DJ, Dewey SL, et al. Opioid receptor imaging and displacement studies with [6-O-[11C]methyl]buprenorphine in baboon brain. Nucl Med Biol. 1996;23:325–331
  109. Shiue CY, Bai LQ, Teng RR, et al. A comparison of the brain uptake of N-(cyclopropyl [11C]methyl)norbuprenorphine ([11C]buprenorphine) and N-(cyclopropyl[11C]methyl) nordiprenorphine ([11C]diprenorphine) in baboon using PET. Nucl Med Biol. 1991;18:281–288
  110. Channing M, Eckelman WC, Bennett JM, et al. Radiosynthesis of [18F]3-acetylcyclofoxy: A high affinity opiate antagonist. Int J Appl Radiat Isot. 1985;36:429–433
  111. Carson RE, Basberg RG, Channing MA, et al. Tracer infusion for equilibrium measurements: Applications to 18F-cyclofoxy opiate receptor imaging with PET. J Cereb Blood Flow Metab. 1989;9(suppl 1):2–203
  112. Kling MA, Carson RE, Borg L, et al. Opioid receptor imaging with positron emission tomography and [18F]cyclofoxy in long-term, methadone-treated former heroin addicts. J Pharmacol Exp Ther. 2000;295:1070–1076
  113. Ravert HT, Mathews WB, Musachio JL, et al. [11C]-Methyl 4-[(3,4-dichlorophenyl) acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylate ([11C]GR89696): Synthesis and in vivo binding to kappa opiate receptors. Nucl Med Biol. 1999;26:737–741
  114. Madar I, Lever JR, Kinter CM, et al. Imaging of delta opioid receptors in human brain by N1′-[11C]methylnaltrindol and PET. Synapse. 1996;24:19–28
  115. Barnard EA, Skolnick P, Olsen RW, et al. International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acid A receptors: Classification on the basis of subunit structure and receptor function. Pharmacol Rev. 1998;50:291–313
  116. Gavish M, Bachman I, Shoukrun R, et al. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev. 1999;51:630–646
  117. (review) Pike VW, Halldin C, Crouzel C, et al. Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites—Current status. Nucl Med Biol. 1993;20:503–525
  118. Koeppe RA, Holthof VA, Frey KA, et al. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab. 1991;11:735–744
  119. Savic I, Roland P, Sedvall G, et al. In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet. 1988;2:863–866
  120. Junck L, Olson JMM, Cilliax BJ, et al. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol. 1989;26:752–758
  121. Banati RB, Newcombe J, Gunn RN. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: Quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123:2321–2337
  122. Cagnin A, Myers R, Gunn RN, et al. In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion. Brain. 2001;124:2014–2027
  123. Coyle JT, Price DL, DeLong MR. Alzheimer's disease: A disorder of cortical cholinergic innervation. Science. 1983;219:1184–1190
  124. Volkow ND, Ding Y-S, Fowler JS, et al. Imaging brain cholinergic activity with positron emission tomography: Its role in the evaluation of cholinergic treatments in Alzheimer's dementia. Biol Psychiatry. 2001;49:211–220
  125. Eckelman WC. Radiolabeled muscarinic radioligands for in vivo studies. Nucl Med Biol. 2001;28:485–491
  126. Schliebs R, Robner S. Distribution of muscarinic acetylcholine receptors in the CNS. In: Stone TW editors. CNS Neurotransmitters and Neuromodulators: Acetylcholine. Boca Raton, FL: CRC Press; 1995;p. 67–83
  127. Flynn DD, Farrari-DiLeo G, Mash DC, et al. Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer's disease. J Neurochem. 1995;64:1881–1891
  128. Frey KA, Koeppe RA, Mulholland GK. In vivo muscarinic cholinergic receptor imaging in human brain with [11C]scopolamine and positron emission tomography. J Cereb Blood Flow Metab. 1992;12:147–154
  129. Mulholland GK, Kilbourn MK, Sherman P, et al. Synthesis, in vivo biodistribution and dosimetry of [11C]N-methylpiperidinyl benzilate ([11C]NMPB), a muscarinic acetylcholine receptor antagonist. Nucl Med Biol. 1995;22:13–17
  130. Lee KS, Frey KA, Koeppe RA, et al. In vivo quantification of cerebral muscarinic receptors in normal human aging using positron emission tomography and [11C]tropanyl benzilate. J Cereb Blood Flow Metab. 1996;16:303–310
  131. Mulholland GK, Kilbourn MR, Sherman P, et al. Synthesis, in vivo biodistribution and dosimetry of [11C]N-methylpiperidyl benzilate ([11C]NMPB), a muscarinic acetylcholine receptor antagonist. Nucl Med Biol. 1995;22:13–17
  132. Buck A, Mulholland GK, Papadopoulos SM, et al. Kinetic evaluation of positron-emitting muscarinic ligands employing direct carotid injection. J Cereb Blood Flow Metab. 1996;16:1280–1287
  133. Zubieta JK, Koeppe RA, Frey KA, et al. Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PET. Synapse. 2001;39:275–287
  134. Yoshida T, Kuwabara Y, Ichiya Y, et al. Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer's disease patients on [11C]-N-methyl-4-piperidinyl benzilate—Comparison with cerebral blood flow and cerebral glucose metabolism. Ann Nucl Med. 1998;12:35–42
  135. Tsukada H, Takahashi K, Miura S, et al. Evaluation of novel PET ligands (+)N-[11C]methyl-3-piperidinyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](−)3-MPB for muscarinic cholinergic receptors in the conscious monkey brain: A PET study in comparison with [11C]4-MPB. Synapse. 2001;39:182–192
  136. Kiesewetter DO, Lee J, Lang L, et al. Preparation of 18F-labeled muscarinic agonist with M2 selectivity. J Med Chem. 1995;38:5–8
  137. Carson RE, Kiesewetter DO, Jagoda E, et al. Muscarinic cholinergic receptor measurements with [18F]FP-TZTP: Control and competition studies. J Cereb Blood Flow Metab. 1998;18:1130–1142
  138. Bonnot-Lours S, Crouzel C, Prenant C, et al. Carbon-11 labelling of an inhibitor of acetylcholinesterase. J Label Compound Radiopharm. 1993;33:277–284
  139. Pappata S, Tavitian B, Traykov L, et al. In vivo imaging of human cerebral acetylcholinesterase. J Neurochem. 1996;67:876–879
  140. Irie T, Fukushi K, Akimoto Y, et al. Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AChE) in vivo. Nucl Med Biol. 1994;21:801–808
  141. Kilbourn MR, Snyder SF, Sherman PS, et al. In vivo studies of acetylcholinesterase activity using a labeled substrate N-[11C]methylpiperidin-4-yl propionate ([11C]PMP). Synapse. 1996;22:123–131
  142. Ingvar M, Stone-Elander S, Rogers GA, et al. Striatal D2/acetylcholine interactions: PET studies of the vesamicol receptor. Neuroreport. 1993;4:1311–1314
  143. Gage HD, Voytko ML, Ehrenkaufer RL, et al. Reproducibility of repeated measures of cholinergic terminal density using [18F](+)-4-fluorobenzyltrozamicol and PET in Rhesus monkey. brain. 2000;41:2069–2076
  144. Sihver W, Nordberg A, Langstrom B, et al. Development of ligands for in vivo imaging of cerebral nicotinic receptors. Behav Brain Res. 2000;113:143–157
  145. Gopalakrishnan M, Donnelly-Roberts DL. Nicotine: Therapeutic prospects?. Pharm News. 1998;5:16–20
  146. Domino EF. Tobacco smoking and nicotine neuropsychopharmacology: Some future research directions. Neuropsychopharmacology. 1998;18:456–468
  147. Arneric SP, Sullivan JP, Williams M. Neuronal nicotinic acetylcholine receptors—Novel targets for central nervous system therapeutics. In: Bloom FE, Kupfer DJ editor. Psychopharmacology: The Fourth Generation of Progress, chapter 9. New York, NY: Raven Press; 1995;p. 95–110
  148. Picciotto MR, Zoli M, Rimondini R, et al. Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature. 1998;391:173–177
  149. Nordberg A. Human nicotinic receptors—Their role in aging and dementia. Neurochem Int. 1994;25:93–97
  150. Perry DC, Davila-Garcia MI, Stockmeier CA, et al. Increased nicotinic receptors in brains from smokers: Membrane binding and autoradiography studies. J Pharmacol Exp Ther. 1999;289:1545–1552
  151. Halldin C, Nagren K, Swahn CG, et al. (S)- and (R)-[11C]nicotine and the metabolite (RS)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET. Int J Rad Appl Instrum /B/. 1992;19:871–880
  152. Nyback H, Nordberg A, Langstrom B, et al. Attempts to visualize nicotinic receptors in the brain of monkey and man by positron emission tomography. Prog Brain Res. 1989;79:313–319
  153. Muzik RF, Berridge MS, Friedland RF, et al. PET quantification of specific binding of carbon-11-nicotine in human brain. J Nucl Med. 1998;39:2048–2054
  154. Sihver W, Fasth J, Ogren M, et al. In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)-(−)[11C] nicotine in rhesus monkeys. Nucl Med Biol. 1999;26:633–642
  155. Spande TF, Garraffo HM, Edwards MW, et al. Epibatidine: a novel (chloropyridyl) azabicycloheptane with potent analgesic activity from the Ecuadoran poison frog. J Am Chem Soc. 1992;114:3475–3478
  156. Qian C, Li T, Shen TY, et al. Epibatidine is a nicotinic analgesic. Eur J Pharmacol. 1993;250:R13–R14
  157. Ding Y-S, Gatley SJ, Fowler JS, et al. Mapping nicotinic acetylcholine receptors with PET. Synapse. 1996;24:403–407
  158. Horti A, Ravert HT, London ED, et al. Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: (±)-Exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane. J Label Compound Radiopharm. 1996;38:355–365
  159. Ding Y-S, Volkow ND, Logan J, et al. Occupancy of brain nicotinic acetylcholine receptors by nicotine doses equivalent to those obtained when smoking a cigarette. Synapse. 2000;35:234–237
  160. Ding Y-S, Logan J, Bermel R, et al. Dopamine receptor-mediated regulation of striatal cholinergic activity: PET studies with [18F]norchlorofluoroepibatidine. J Neurochem. 2000;74:1514–1521
  161. Ding Y-S, Molina PE, Fowler JS, et al. Comparative studies of epibatidine derivatives [18F]NFEP and [18F]N-methyl-NEEP: Kinetics, nicotine effect and toxicity. Nucl Med Biol. 1999;26:139–148
  162. Molina PE, Ding Y-S, Carroll FI, et al. Fluoro-norchloroepibatidine: Preclinical assessment of acute toxicity. Nucl Med Biol. 1997;24:743–747
  163. Abreo MA, Lin N-H, Garvey DS, et al. Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors. J Med Chem. 1996;39:817–825
  164. Valette H, Bottlaender M, Dolle F, et al. Imaging central nicotinic acetylcholine receptors in baboons with [18F]fluoro-A-85380. J Nucl Med. 1999;40:1374–1380
  165. Horti AG, Koren AO, Ravert HT, et al. Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]A- 85380). J Label Compound Radiopharm. 1998;41:300–318
  166. Dolle F, Valette H, Bottlaender M, et al. Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidimylmethoxy]pyridine a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors. J Label Compound Radiopharm. 1998;41:451–463
  167. Dolle F, Dolci L, Valette H, et al. Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: A new positron emission tomography ligand for nicotinic receptors. J Med Chem. 1999;42:2251–2259
  168. Koren AO, Horti AG, Mukhin AG, et al. Synthesis and in vitro characterization of 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine, a high-affinity radioligand for central nicotinic acetylcholine receptors. J Label Compound Radiopharm. 1999;42:S409–S410
  169. Scheffel U, Horti AG, Koren AO, et al. 6-[18F]Fluoro-A-85380: An in vivo tracer for the nicotinic acetylcholine receptor. Nucl Med Biol. 2000;27:51–56
  170. Ding Y-S, Liu N, Wang T, et al. Synthesis of 6-[18F]fluoro-3-(S)-azetidinylmethoxy) pyridine for PET studies of nicotine acetylcholine receptors. Nucl Med Biol. 2000;27:381–389
  171. Duman RS, Nestler EJ. Signal transduction pathways for catecholamine receptors. In: Meltzer H editors. Psychopharmacology: The Fourth Generation. New York, NY: Raven Press; 1995;p. 303–320
  172. Imahori Y, Ohmori Y, Fujii R, et al. Rapid incorporation of carbon-11 labeled diacylglycerol as a probe of signal transduction in glioma. Cancer Res. 1995;55:4225–4229
  173. Sasaki T, Enta A, Nozaki T, et al. Carbon-11-forskolin: A ligand for visualization of the adenylate cyclase-related second messenger. J Nucl Med. 1993;34:1944–1948
  174. Takahashi T, Ootake A. [18F]Labeled 1,2-diacylglycerols: A new tracer for imaging second messenger system. J Label Compound Radiopharm. 1994;35:517–519
  175. Lourenco CM, DaSilva J, Warsh JJ, et al. Imaging of cAMP-specific phosphodiesterase-IV: Comparison of [11C]rolipam and [11C]Ro 20-1724 in rats. Synapse. 1999;31:41–50
  176. Lourenco CM, Houle S, Wilson AA, et al. Characterization of R-[11C]rolipam for PET imaging of phosphodiesterase-4: In vivo binding, metabolism and dosimetry studies in rats. Nucl Med Biol. 2001;28:347–358
  177. Vaalburg W, Coenen HH, Crouzel C, et al. Amino acids for the measurement of protein synthesis in vivo by PET. Nucl Med Biol. 1992;19:227–237
  178. Jager PL, Vaalburg W, Prium J, et al. Radiolabeled amino acids: Basic aspects and clinical applications in oncology. J Nucl Med. 2001;42:432–445
  179. Hawkins RA, Huang S-C, Barrio JR, et al. Estimation of local cerebral protein synthesis rates with l-[1-11C]leucine and PET: Methods, model, and results in animals and humans. J Cereb Blood Flow Metab. 1989;9:446–460
  180. Smith CB, Davidsen L, Deibler G, et al. A method for the determination of local rates of protein synthesis in man. Trans Am Soc Neurochem. 1980;11:94
  181. Smith CB, Deibler GE, Eng N, et al. Measurement of local cerebral protein synthesis in vivo: Influence of recycling of amino acids derived from protein degradation. In: Proc Natl Acad Sci USA. 85:1988;p. 9341–9345
  182. Schober O, Duden C, Meyer G-J, et al. Nonselective transport of [11C]methyl]-l-and d-methionine into a malignant glioma. Eur J Nucl Med. 1987;13:103–105
  183. Bergstrom M, Muhr C, Lundberg PO, et al. Amino acid distribution and metabolism in pituitary adenomas using positron emission tomography with d-[11C]methionine and l-[11C]methionine. J Comput Assist Tomogr. 1987;11:384–389
  184. Bodsch W, Coenen HH, Stocklin G, et al. Biochemical and autoradiographic study of cerebral protein synthesis with [18F]- and [14C]fluorophenylalanine. J Neurochem. 1988;50:979–983
  185. Coenen HH, Kling P, Stocklin G. Cerebral metabolism of l-2-[18F]fluorotyrosine, a new PET tracer for protein synthesis. J Nucl Med. 1989;30:1367–1372
  186. Ishiwata K, Kubota K, Murakami M, et al. Re-evaluation of amino acid PET studies: Can the protein synthesis rates in brain and tumor tissues be measured in vivo?. J Nucl Med. 1993;34:1936–1943
  187. Weinhard K, Herholz K, Coenen HH, et al. Increased amino acid transport into brain tumors measured by PET of l-(2-18F)fluorotyrosine. J Nucl Med. 1991;32:1338–1346
  188. Ogawa T, Miura S, Murakami M, et al. Quantitative evaluation of neutral amino acid transport in cerebral gliomas using positron emission tomography and fluorine-18 fluorophenylalanine. Eur J Nucl Med. 1996;23:889–895
  189. Wester HJ, Herz M, Weber W, et al. Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-l-tyrosine for tumor imaging. J Nucl Med. 1999;40:205–212
  190. Tomiyoshi K, Amed K, Muhammed S, et al. Synthesis of isomers of 18F-labelled amino acid radiopharmaceutical: Position 2- and 3-l-18F-alpha-methyltyrosine using a separation and purification system. Nucl Med Commun. 1997;18:169–175
  191. Inoue TJ, Shibasaki T, Oriuchi N, et al. 18F-α-methyl tyrosine PET studies in patients with brain tumors. J Nucl Med. 1999;40:399–405
  192. Inoue TJ, Tomiyoshi K, Higuchi T, et al. Biodistribution studies on l-3-[fluorine-18] fluoro-α-methyl tyrosine: A potential tumor-detecting agent. J Nucl Med. 1998;39:663–667
  193. Shoup TM, Olson JMH, Votaw J, et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors. J Nucl Med. 1999;40:331–338
  194. Cronkite EP, Fliedner TM, Bond VP, et al. Dynamics of hemopoietic proliferation in man and mice studied by 3H-thymidine incorporation into DNA. Ann N Y Acad Sci. 1959;77:803–820
  195. Christman DR, Crawford EJ, Friedkin M, et al. Detection of DNA synthesis in intact organisms with positron-emitting methyl 11C-thymidine. In: Proc Natl Acad Sci USA. 69:1971;p. 988–989
  196. Crawford EJ, Friedkin M, Wolf AP, et al. 18F-5-Fluorouridine, a new probe for measuring the proliferation of tissue in vivo. Adv Enzyme Regul. 1982;20:3–22
  197. Shields AF, Coonrod DV, Quackenbush RC, et al. Cellular sources of thymidine nucleotides: Studies for PET. J Nucl Med. 1987;28:1435–1440
  198. Shields AF, Larson SM, Grunbaum Z, et al. Short-term thymidine uptake in normal and neoplastic tissues: Studies for PET. J Nucl Med. 1984;25:759–764
  199. Mankoff DA, Dehdashti F, Shields AF. Characterizing tumors using metabolic imaging: PET imaging of cellular proliferation and steroid receptors. Neoplasia. 2000;2:71–88
  200. Shields AF, Mankoff DA, Link JM, et al. Carbon-11-thymidine and FDG to measure therapy response. J Nucl Med. 1989;39:1757–1762
  201. Mankoff DA, Shields AF, Link JM, et al. Kinetic analysis of 2-[11C]thymidine PET imaging studies: Validation studies. J Nucl Med. 1999;40:614–624
  202. Eary JF, Mankoff DA, Spence AM, et al. 2-[C-11]Thymidine imaging of malignant brain tumors. Cancer Res. 1999;5:615–621
  203. Shields AF, Lim K, Grierson J, et al. Utilization of labeled thymidine in DNA synthesis: Studies for PET. J Nucl Med. 1990;31:337–342
  204. Shields AF, Grierson JR, Kozawa SM, et al. Development of labeled thymidine analogs for imaging tumor proliferation. Nucl Med Biol. 1996;23:17–22
  205. Conti PS, Alauddin MM, Fissekis JR, et al. Synthesis of 2′-fluoro-5-[11C]-methyl-1-beta-d-arabinofuranosyluracil ([11C]-FMAU): A potential nucleoside analog for in vivo study of cellular proliferation with PET. Nucl Med Biol. 1995;22:783–789
  206. Grierson JR, Shields AF. Radiosynthesis of 3′-deoxy-3′[18F]fluorothymidine: [18F]FLT for imaging of cellular proliferation in vivo. Nucl Med Biol. 2000;27:143–156
  207. Kong XB, Zhu QY, Vidal PM, et al. Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine. Antimicrob Agents Chemother. 1992;36:808–818
  208. Shields AF, Grierson JR, Dohmen BM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998;4:1334–1336
  209. DeGrado TR, Coleman RE, Wang S, et al. Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: Initial findings in prostate cancer. Cancer Res. 2001;61:110–117
  210. Raffel DM, Wieland DM. Assessment of cardiac sympathetic nerve integrity with positron emission tomography. Nucl Med Biol. 2001;28:541–559
  211. Ding Y-S, Fowler JS, Dewey SL, et al. Comparison of high specific activity (-)- and (+)-6-[18F]fluoronorepinephrine and 6-[18F]fluorodopamine in baboons: Heart uptake, metabolism and the effect of desipramine. J Nucl Med. 1993;34:619–629
  212. Haka MS, Kilbourn MR. Synthesis and regional mouse brain distribution of [11C]nisoxetine, a norepinephrine uptake inhibitor. Int J Rad Appl Instrum B. 1989;16:771–774
  213. Yaghoubi S, Barrio JR, Dahlbom M, et al. Human pharmacokinetic and dosimetry studies of [18F]FHBG: A reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. J Nucl Med. 2001;42:1225–1234
  214. Berger F, Gambhir SS. Recent advances in imaging endogenous or transferred gene expression utilizing radionuclide technologies in living subjects: Application in breast cancer. Breast Cancer Res. 2001;3:28–35
  215. Kuhnast B, Dolle F, Terrazzino S, et al. General method to label antisense oligonucleotides with radioactive halogens for pharmacological and imaging studies. Bioconjug Chem. 2000;11:627–636
  216. Agdeppa ED, Kepe V, Liu J, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylidene derivatives as positron emission tomography imaging probes for β-amyloid plaques in Alzheimer's disease. J Neurosci. 2001;21:RC189
  217. Klunk WE, Wang Y, Huang GF, et al. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci. 2001;69:1471–1484
  218. Zhuang ZP, Kung MP, Hou C, et al. IBOX(2-(4′-dimethyl-aminophenyl)-6-iodobenzoxazole): A ligand for imaging amyloid plaques in the brain. Nucl Med Biol. 2001;28:887–894
  219. McEwen B. Editorial comment: The ever-changing brain. Neuropsychopharmacology. 2001;25:797–798

** Much of this work was performed at Brookhaven National Laboratory under Contract DE-AC02-98CH10886 with the US Department of Energy and was supported by its Office of Biological and Environmental Research and the National Institutes of Health (National Institutes of Neurological Diseases and Stroke Grant NS15380).

PII: S0001-2998(03)80003-X

doi: 10.1053/snuc.2003.127297

Seminars in Nuclear Medicine
Volume 33, Issue 1 , Pages 14-27 , January 2003