Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2014 Aug 29;30(5):777–811. doi: 10.1007/s12264-014-1460-6

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Peter Brust 1,✉, Jörg van den Hoff 1, Jörg Steinbach 1
PMCID: PMC5562586  PMID: 25172118

Abstract

Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically-engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.

Keywords: Alzheimer’s disease, autoradiography, blood-brain barrier, brain tumor, cholinergic system, kinetic modeling, metabolism, molecular imaging, neurodegeneration, positron emission tomography, precursor, psychiatric disorder, radiotracer, sigma receptor

References

  • [1].Mankoff DA. A definition of molecular imaging. J Nucl Med. 2007;48:18N. [PubMed] [Google Scholar]
  • [2].Pichler BJ, Judenhofer MS, Pfannenberg C. Handb Exp Pharmacol. 2008. Multimodal imaging approaches: PET/CT and PET/MRI; pp. 109–132. [DOI] [PubMed] [Google Scholar]
  • [3].Drzezga A, Barthel H, Minoshima S, Sabri O. Potential clinical applications of PET/MR imaging in neurodegenerative diseases. J Nucl Med. 2014;55:1–9. doi: 10.2967/jnumed.113.129254. [DOI] [PubMed] [Google Scholar]
  • [4].Levi H. George von Hevesy memorial lecture. George Hevesy and his concept of radioactive indicators—in retrospect. Eur J Nucl Med. 1976;1:3–10. doi: 10.1007/BF00253259. [DOI] [PubMed] [Google Scholar]
  • [5].Sampson CD, editor. Textbook of Radiopharmacy: Theory and Practice. 3rd. ed. Amsterdam: Gordan and Breach Science Publishers; 1999. [Google Scholar]
  • [6].Brust P, Deuther-Conrad W, Donat CK, Barthel H, Riss P, Paterson L, et al. et al. Preclinical aspects of nicotinic acetylcholine receptor imaging. In: Dierckx RAJ, Otte A, de Vries EFJ, et al.et al., editors. PET and SPECT of Neurobiological Systems. 2014. pp. 465–512. [Google Scholar]
  • [7].Virdee K, Cumming P, Caprioli D, Jupp B, Rominger A, Aigbirhio FI, et al. Applications of positron emission tomography in animal models of neurological and neuropsychiatric disorders. Neurosci Biobehav Rev. 2012;36:1188–1216. doi: 10.1016/j.neubiorev.2012.01.009. [DOI] [PubMed] [Google Scholar]
  • [8].Melhem M. Translation of central nervous system occupancy from animal models: application of pharmacokinetic/pharmacodynamic modeling. J Pharmacol Exp Ther. 2013;347:2–6. doi: 10.1124/jpet.112.199794. [DOI] [PubMed] [Google Scholar]
  • [9].Frey KA, Koeppe RA, Mulholland GK, Jewett D, Hichwa R, Ehrenkaufer RL, et al. 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. doi: 10.1038/jcbfm.1992.18. [DOI] [PubMed] [Google Scholar]
  • [10].Xie G, Gunn RN, Dagher A, Daloze T, Plourde G, Backman SB, et al. PET quantification of muscarinic cholinergic receptors with [N-11C-methyl]-benztropine and application to studies of propofol-induced unconsciousness in healthy human volunteers. Synapse. 2004;51:91–101. doi: 10.1002/syn.10292. [DOI] [PubMed] [Google Scholar]
  • [11].Yamamoto S, Ouchi Y, Nakatsuka D, Tahara T, Mizuno K, Tajima S, et al. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012;7:e51515. doi: 10.1371/journal.pone.0051515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Ichise M, Cohen RM, Carson RE. Noninvasive estimation of normalized distribution volume: application to the muscarinic-2 ligand [18F]FP-TZTP. J Cereb Blood Flow Metab. 2008;28:420–430. doi: 10.1038/sj.jcbfm.9600530. [DOI] [PubMed] [Google Scholar]
  • [13].Sabri O, Kendziorra K, Wolf H, Gertz HJ, Brust P. Acetylcholine receptors in dementia and mild cognitive impairment. Eur J Nucl Med Mol Imaging. 2008;35(Suppl1):S30–45. doi: 10.1007/s00259-007-0701-1. [DOI] [PubMed] [Google Scholar]
  • [14].Ding YS, Fowler JS, Logan J, Wang GJ, Telang F, Garza V, et al. 6-[18F]Fluoro-A-85380, a new PET tracer for the nicotinic acetylcholine receptor: studies in the human brain and in vivo demonstration of specific binding in white matter. Synapse. 2004;53:184–189. doi: 10.1002/syn.20051. [DOI] [PubMed] [Google Scholar]
  • [15].Wong DF, Kuwabara H, Kim J, Brasic JR, Chamroonrat W, Gao Y, et al. PET imaging of high-affinity α4β2 nicotinic acetylcholine receptors in humans with 18F-AZAN, a radioligand with optimal brain kinetics. J Nucl Med. 2013;54:1308–1314. doi: 10.2967/jnumed.112.108001. [DOI] [PubMed] [Google Scholar]
  • [16].Sabri O, Wilke S, Gräf S, Schönknecht P, Becker G, Patt M, et al. Cerebral α4β2 nicotinic acetylcholine receptors (nAChRs) in early Alzheimer disease (AD) assessed with the new PET tracer (-)-[18F]-norchloro-fluoro-homoepibatidine (NCFHEB) J Nucl Med. 2011;52(Suppl.1):1267. [Google Scholar]
  • [17].Toyohara J, Sakata M, Wu J, Ishikawa M, Oda K, Ishii K, et al. Preclinical and the first clinical studies on [11C] CHIBA-1001 for mapping α7 nicotinic receptors by positron emission tomography. Ann Nucl Med. 2009;23:301–309. doi: 10.1007/s12149-009-0240-x. [DOI] [PubMed] [Google Scholar]
  • [18].Bauer A, Holschbach MH, Meyer PT, Boy C, Herzog H, Olsson RA, et al. In vivo imaging of adenosine A1 receptors in the human brain with [18F]CPFPX and positron emission tomography. Neuroimage. 2003;19:1760–1769. doi: 10.1016/s1053-8119(03)00241-6. [DOI] [PubMed] [Google Scholar]
  • [19].Fukumitsu N, Ishii K, Kimura Y, Oda K, Hashimoto M, Suzuki M, et al. Adenosine A1 receptors using 8-dicyclopropylmethyl-1-[11C]methyl-3-propylxanthine PET in Alzheimer’s disease. Ann Nucl Med. 2008;22:841–847. doi: 10.1007/s12149-008-0185-5. [DOI] [PubMed] [Google Scholar]
  • [20].Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, et al. Adenosine A2A receptors measured with [11C] TMSX PET in the striata of Parkinson’s disease patients. PLoS One. 2011;6:e17338. doi: 10.1371/journal.pone.0017338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology. 2011;76:1811–1816. doi: 10.1212/WNL.0b013e31821ccce4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Burns HD, Van Laere K, Sanabria-Bohorquez S, Hamill TG, Bormans G, Eng WS, et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci U S A. 2007;104:9800–9805. doi: 10.1073/pnas.0703472104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Terry GE, Hirvonen J, Liow JS, Seneca N, Tauscher JT, Schaus JM, et al. Biodistribution and dosimetry in humans of two inverse agonists to image cannabinoid CB1 receptors using positron emission tomography. Eur J Nucl Med Mol Imaging. 2010;37:1499–1506. doi: 10.1007/s00259-010-1411-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Wong DF, Kuwabara H, Horti AG, Raymont V, Brasic J, Guevara M, et al. Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage. 2010;52:1505–1513. doi: 10.1016/j.neuroimage.2010.04.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Ahmad R, Koole M, Evens N, Serdons K, Verbruggen A, Bormans G, et al. Mol Imaging Biol. 2013. Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. [DOI] [PubMed] [Google Scholar]
  • [26].Farde L, Halldin C, Stone-Elander S, Sedvall G. PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride. Psychopharmacology. 1987;92:278–284. doi: 10.1007/BF00210831. [DOI] [PubMed] [Google Scholar]
  • [27].Karlsson P, Farde L, Halldin C, Swahn CG, Sedvall G, Foged C, et al. PET examination of [11C]NNC 687 and [11C] NNC 756 as new radioligands for the D1-dopamine receptor. Psychopharmacology. 1993;113:149–156. doi: 10.1007/BF02245691. [DOI] [PubMed] [Google Scholar]
  • [28].Slifstein M, Kolachana B, Simpson EH, Tabares P, Cheng B, Duvall M, et al. COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET. Mol Psychiatry. 2008;13:821–827. doi: 10.1038/mp.2008.19. [DOI] [PubMed] [Google Scholar]
  • [29].Farde L, Hall H, Ehrin E, Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science. 1986;231:258–261. doi: 10.1126/science.2867601. [DOI] [PubMed] [Google Scholar]
  • [30].Wong DF, Wagner HN, Jr., Tune LE, Dannals RF, Pearlson GD, Links JM, et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science. 1986;234:1558–1563. doi: 10.1126/science.2878495. [DOI] [PubMed] [Google Scholar]
  • [31].Narendran R, Frankle WG, Mason NS, Laymon CM, Lopresti BJ, Price JC, et al. Positron emission tomography imaging of D2/3 agonist binding in healthy human subjects with the radiotracer [11C]-N-propyl-norapomorphine: preliminary evaluation and reproducibility studies. Synapse. 2009;63:574–584. doi: 10.1002/syn.20633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Otsuka T, Ito H, Halldin C, Takahashi H, Takano H, Arakawa R, et al. Quantitative PET analysis of the dopamine D2 receptor agonist radioligand 11C-(R)-2-CH3O-N-npropylnorapomorphine in the human brain. J Nucl Med. 2009;50:703–710. doi: 10.2967/jnumed.108.058503. [DOI] [PubMed] [Google Scholar]
  • [33].Farde L, Suhara T, Nyberg S, Karlsson P, Nakashima Y, Hietala J, et al. A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients. Psychopharmacology. 1997;133:396–404. doi: 10.1007/s002130050420. [DOI] [PubMed] [Google Scholar]
  • [34].Mukherjee J, Christian BT, Dunigan KA, Shi B, Narayanan TK, Satter M, et al. Brain imaging of 18F-fallypride in normal volunteers: blood analysis, distribution, test-retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D-2/D-3 receptors. Synapse. 2002;46:170–188. doi: 10.1002/syn.10128. [DOI] [PubMed] [Google Scholar]
  • [35].Ginovart N, Willeit M, Rusjan P, Graff A, Bloomfield PM, Houle S, et al. Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain. J Cereb Blood Flow Metab. 2007;27:857–871. doi: 10.1038/sj.jcbfm.9600411. [DOI] [PubMed] [Google Scholar]
  • [36].Moresco RM, Scheithauer BW, Lucignani G, Lombardi D, Rocca A, Losa M, et al. Oestrogen receptors in meningiomas: a correlative PET and immunohistochemical study. Nucl Med Comm. 1997;18:606–615. doi: 10.1097/00006231-199707000-00003. [DOI] [PubMed] [Google Scholar]
  • [37].Toyohara J, Sakata M, Fujinaga M, Yamasaki T, Oda K, Ishii K, et al. Preclinical and the first clinical studies on [11C] ITMM for mapping metabotropic glutamate receptor subtype 1 by positron emission tomography. Nucl Med Biol. 2013;40:214–220. doi: 10.1016/j.nucmedbio.2012.11.008. [DOI] [PubMed] [Google Scholar]
  • [38].Ametamey SM, Treyer V, Streffer J, Wyss MT, Schmidt M, Blagoev M, et al. Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J Nucl Med. 2007;48:247–252. [PubMed] [Google Scholar]
  • [39].Brown AK, Kimura Y, Zoghbi SS, Simeon FG, Liow JS, Kreisl WC, et al. Metabotropic glutamate subtype 5 receptors are quantified in the human brain with a novel radioligand for PET. J Nucl Med. 2008;49:2042–2048. doi: 10.2967/jnumed.108.056291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Kagedal M, Cselenyi Z, Nyberg S, Jonsson S, Raboisson P, Stenkrona P, et al. Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers. Neuroimage. 2012;61:849–856. doi: 10.1016/j.neuroimage.2012.02.085. [DOI] [PubMed] [Google Scholar]
  • [41].Wong DF, Waterhouse R, Kuwabara H, Kim J, Brasic JR, Chamroonrat W, et al. 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med. 2013;54:388–396. doi: 10.2967/jnumed.112.107995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Kumlien E, Hartvig P, Valind S, Oye I, Tedroff J, Langström B. NMDA-receptor activity visualized with (S)-[N-methyl-11C] ketamine and positron emission tomography in patients with medial temporal lobe epilepsy. Epilepsia. 1999;40:30–37. doi: 10.1111/j.1528-1157.1999.tb01985.x. [DOI] [PubMed] [Google Scholar]
  • [43].Hammers A, Asselin M, Brooks DJ, Luthra SK, Hume SP, Thompson PJ, et al. Correlation of memory function with binding of [C-11]CNS 5161, a novel putative NMDA ion channel PET ligand. Neuroimage. 2004;22(Suppl2):T54–55. [Google Scholar]
  • [44].Ametamey SM, Bruehlmeier M, Kneifel S, Kokic M, Honer M, Arigoni M, et al. PET studies of 18F-memantine in healthy volunteers. Nucl Med Biol. 2002;29:227–231. doi: 10.1016/s0969-8051(01)00293-1. [DOI] [PubMed] [Google Scholar]
  • [45].McGinnity CJ, Hammers A, Riano Barros DA, Luthra SK, Jones PA, Trigg W, et al. Initial evaluation of 18F-GE-179, a putative PET Tracer for activated N-methyl D-aspartate receptors. J Nucl Med. 2014;55:423–430. doi: 10.2967/jnumed.113.130641. [DOI] [PubMed] [Google Scholar]
  • [46].Matsumoto R, Haradahira T, Ito H, Fujimura Y, Seki C, Ikoma Y, et al. Measurement of glycine binding site of N-methyl-D-asparate receptors in living human brain using 4-acetoxy derivative of L-703,717, 4-acetoxy-7-chloro-3-[3-(4-[11C] methoxybenzyl) phenyl]-2(1H)-quinolone (AcL703) with positron emission tomography. Synapse. 2007;61:795–800. doi: 10.1002/syn.20415. [DOI] [PubMed] [Google Scholar]
  • [47].Yanai K, Watanabe T, Itoh M, Hatazawa J, Iwata R, Ido T. Labeling of histamine H1-receptors in vivo: a compartment model analysis and positron emission tomographic imaging. Agents Actions Suppl. 1991;33:381–386. doi: 10.1007/978-3-0348-7309-3_27. [DOI] [PubMed] [Google Scholar]
  • [48].Ashworth S, Rabiner EA, Gunn RN, Plisson C, Wilson AA, Comley RA, et al. Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med. 2010;51:1021–1029. doi: 10.2967/jnumed.109.071753. [DOI] [PubMed] [Google Scholar]
  • [49].Persson A, Ehrin E, Eriksson L, Farde L, Hedström CG, Litton JE, et al. Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatric Res. 1985;19:609–622. doi: 10.1016/0022-3956(85)90080-9. [DOI] [PubMed] [Google Scholar]
  • [50].Leveque P, Sanabria-Bohorquez S, Bol A, De Volder A, Labar D, Van Rijckevorsel K, et al. Quantification of human brain benzodiazepine receptors using [18F]fluoroethylflumazenil: a first report in volunteers and epileptic patients. Eur J Nucl Med Mol Imaging. 2003;30:1630–1636. doi: 10.1007/s00259-003-1304-0. [DOI] [PubMed] [Google Scholar]
  • [51].Lee JD, Park HJ, Park ES, Kim DG, Rha DW, Kim EY, et al. Assessment of regional GABAA receptor binding using 18F-fluoroflumazenil positron emission tomography in spastic type cerebral palsy. Neuroimage. 2007;34:19–25. doi: 10.1016/j.neuroimage.2006.09.004. [DOI] [PubMed] [Google Scholar]
  • [52].Massaweh G, Schirrmacher E, la Fougere C, Kovacevic M, Wängler C, Jolly D, et al. Improved work-up procedure for the production of [18F]flumazenil and first results of its use with a high-resolution research tomograph in human stroke. Nucl Med Biol. 2009;36:721–727. doi: 10.1016/j.nucmedbio.2009.05.008. [DOI] [PubMed] [Google Scholar]
  • [53].Lingford-Hughes A, Hume SP, Feeney A, Hirani E, Osman S, Cunningham VJ, et al. Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. J Cereb Blood Flow Metab. 2002;22:878–889. doi: 10.1097/00004647-200207000-00013. [DOI] [PubMed] [Google Scholar]
  • [54].Frost JJ, Mayberg HS, Sadzot B, Dannals RF, Lever JR, Ravert HT, et al. Comparison of [11C]diprenorphine and [11C] carfentanil binding to opiate receptors in humans by positron emission tomography. J Cereb Blood Flow Metab. 1990;10:484–492. doi: 10.1038/jcbfm.1990.90. [DOI] [PubMed] [Google Scholar]
  • [55].Madar I, Lesser RP, Krauss G, Zubieta JK, Lever JR, Kinter CM, et al. Imaging of σ- and μ-opioid receptors in temporal lobe epilepsy by positron emission tomography. Ann Neurol. 1997;41:358–367. doi: 10.1002/ana.410410311. [DOI] [PubMed] [Google Scholar]
  • [56].Tomasi G, Zheng M-Q, Weinzimmer D, Lin S-F, Nabulsi N, Williams W, et al. Kinetic modeling of the kappa agonist tracer [11C]GR103545 in humans. J Nucl Med. 2010;51(Supplement2):1293. [Google Scholar]
  • [57].Cohen RM, Carson RE, Sunderland T. Opiate receptor avidity in the thalamus is sexually dimorphic in the elderly. Synapse. 2000;38:226–229. doi: 10.1002/1098-2396(200011)38:2<226::AID-SYN13>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  • [58].Baumgärtner U, Buchholz HG, Bellosevich A, Magerl W, Siessmeier T, Rolke R, et al. High opiate receptor binding potential in the human lateral pain system. Neuroimage. 2006;30:692–699. doi: 10.1016/j.neuroimage.2005.10.033. [DOI] [PubMed] [Google Scholar]
  • [59].Hostetler ED, Sanabria-Bohorquez S, Fan H, Zeng Z, Gantert L, Williams M, et al. Synthesis, characterization, and monkey positron emission tomography (PET) studies of [18F]Y1-973, a PET tracer for the neuropeptide Y Y1 receptor. Neuroimage. 2011;54:2635–2642. doi: 10.1016/j.neuroimage.2010.11.014. [DOI] [PubMed] [Google Scholar]
  • [60].Pike VW, McCarron JA, Lammerstma AA, Hume SP, Poole K, Grasby PM, et al. First delineation of 5-HT1A receptors in human brain with PET and 11C WAY-100635. Eur J Pharmacol. 1995;283:R1–3. doi: 10.1016/0014-2999(95)00438-q. [DOI] [PubMed] [Google Scholar]
  • [61].Parsey RV, Slifstein M, Hwang DR, Abi-Dargham A, Simpson N, Mawlawi O, et al. Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions. J Cereb Blood Flow Metab. 2000;20:1111–1133. doi: 10.1097/00004647-200007000-00011. [DOI] [PubMed] [Google Scholar]
  • [62].Andree B, Halldin C, Pike VW, Gunn RN, Olsson H, Farde L. The PET radioligand [carbonyl-11C]desmethyl-WAY-100635 binds to 5-HT1A receptors and provides a higher radioactive signal than [carbonyl-11C]WAY-100635 in the human brain. J Nucl Med. 2002;43:292–303. [PubMed] [Google Scholar]
  • [63].Houle S, Wilson AA, Inaba T, Fisher N, DaSilva JN. Imaging 5-HT1A receptors with positron emission tomography: initial human studies with [11C]CPC-222. Nucl Med Comm. 1997;18:1130–1134. doi: 10.1097/00006231-199712000-00004. [DOI] [PubMed] [Google Scholar]
  • [64].Milak MS, DeLorenzo C, Zanderigo F, Prabhakaran J, Kumar JS, Majo VJ, et al. In vivo quantification of human serotonin 1A receptor using 11C-CUMI-101, an agonist PET radiotracer. J Nucl Med. 2010;51:1892–1900. doi: 10.2967/jnumed.110.076257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Costes N, Merlet I, Zimmer L, Lavenne F, Cinotti L, Delforge J, et al. Modeling [18F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine1A receptor concentration with multiinjection. J Cereb Blood Flow Metab. 2002;22:753–765. doi: 10.1097/00004647-200206000-00014. [DOI] [PubMed] [Google Scholar]
  • [66].Theodore WH, Giovacchini G, Bonwetsch R, Bagic A, Reeves-Tyer P, Herscovitch P, et al. The effect of antiepileptic drugs on 5-HT-receptor binding measured by positron emission tomography. Epilepsia. 2006;47:499–503. doi: 10.1111/j.1528-1167.2006.00458.x. [DOI] [PubMed] [Google Scholar]
  • [67].Gallezot JD, Nabulsi N, Neumeister A, Planeta-Wilson B, Williams WA, Singhal T, et al. Kinetic modeling of the serotonin 5-HT1B receptor radioligand [11C]P943 in humans. J Cereb Blood Flow Metab. 2010;30:196–210. doi: 10.1038/jcbfm.2009.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [68].Varnäs K, Nyberg S, Halldin C, Varrone A, Takano A, Karlsson P, et al. Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain. J Cereb Blood Flow Metab. 2011;31:113–123. doi: 10.1038/jcbfm.2010.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [69].Murrough JW, Henry S, Hu J, Gallezot JD, Planeta-Wilson B, Neumaier JF, et al. Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder. Psychopharmacology. 2011;213:547–553. doi: 10.1007/s00213-010-1881-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [70].Hinz R, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM. Validation of a tracer kinetic model for the quantification of 5-HT2A receptors in human brain with [11C]MDL 100,907. J Cereb Blood Flow Metab. 2007;27:161–172. doi: 10.1038/sj.jcbfm.9600323. [DOI] [PubMed] [Google Scholar]
  • [71].Rosier A, Dupont P, Peuskens J, Bormans G, Vandenberghe R, Maes M, et al. Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging. Psychiatry Res. 1996;68:11–22. doi: 10.1016/s0925-4927(96)02806-5. [DOI] [PubMed] [Google Scholar]
  • [72].van Dyck CH, Soares JC, Tan PZ, Staley JK, Baldwin RM, Amici LA, et al. Equilibrium modeling of 5-HT2A receptors with [18F]deuteroaltanserin and PET: feasibility of a constant infusion paradigm. Nucl Med Biol. 2000;27:715–722. doi: 10.1016/s0969-8051(00)00160-8. [DOI] [PubMed] [Google Scholar]
  • [73].Trichard C, Paillere-Martinot ML, Attar-Levy D, Recassens C, Monnet F, Martinot JL. Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry. 1998;155:505–508. doi: 10.1176/ajp.155.4.505. [DOI] [PubMed] [Google Scholar]
  • [74].Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, et al. J Cereb Blood Flow Metab. 2014. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [75].Marner L, Gillings N, Comley RA, Baare WF, Rabiner EA, Wilson AA, et al. Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo. J Nucl Med. 2009;50:900–908. doi: 10.2967/jnumed.108.058552. [DOI] [PubMed] [Google Scholar]
  • [76].Parker CA, Gunn RN, Rabiner EA, Slifstein M, Comley R, Salinas C, et al. Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor. J Nucl Med. 2012;53:295–303. doi: 10.2967/jnumed.111.093419. [DOI] [PubMed] [Google Scholar]
  • [77].Mishina M, Ishiwata K, Ishii K, Kitamura S, Kimura Y, Kawamura K, et al. Function of sigma1 receptors in Parkinson’s disease. Acta Neurol Scand. 2005;112:103–107. doi: 10.1111/j.1600-0404.2005.00432.x. [DOI] [PubMed] [Google Scholar]
  • [78].Waterhouse RN, Nobler MS, Zhou Y, Chang RC, Morales O, Kuwabara H, et al. First evaluation of the sigma1 receptor radioligand [18F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl) piperidine ([18F]FPS) in healthy humans. Neuroimage. 2004;22:T29. [Google Scholar]
  • [79].Junck L, Olson JM, Ciliax BJ, Koeppe RA, Watkins GL, Jewett DM, et al. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol. 1989;26:752–758. doi: 10.1002/ana.410260611. [DOI] [PubMed] [Google Scholar]
  • [80].Banati RB, Goerres GW, Myers R, Gunn RN, Turkheimer FE, Kreutzberg GW, et al. [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology. 1999;53:2199–2203. doi: 10.1212/wnl.53.9.2199. [DOI] [PubMed] [Google Scholar]
  • [81].Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH, et al. Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J Nucl Med. 2007;48:2072–2079. doi: 10.2967/jnumed.107.044842. [DOI] [PubMed] [Google Scholar]
  • [82].Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC, et al. Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med. 2009;50:1276–1282. doi: 10.2967/jnumed.109.062265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [83].Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, et al. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [11C]DAA1106. Psychiatry Res. 2012;203:67–74. doi: 10.1016/j.pscychresns.2011.08.013. [DOI] [PubMed] [Google Scholar]
  • [84].Gulyas B, Toth M, Schain M, Airaksinen A, Vas A, Kostulas K, et al. Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [11C]vinpocetine. J Neurol Sci. 2012;320:110–117. doi: 10.1016/j.jns.2012.06.026. [DOI] [PubMed] [Google Scholar]
  • [85].Fujimura Y, Zoghbi SS, Simeon FG, Taku A, Pike VW, Innis RB, et al. Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, F-18-PBR06. J Nucl Med. 2009;50:1047–1053. doi: 10.2967/jnumed.108.060186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [86].Arlicot N, Vercouillie J, Ribeiro MJ, Tauber C, Venel Y, Baulieu JL, et al. Initial evaluation in healthy humans of [18F] DPA-714, a potential PET biomarker for neuroinflammation. Nucl Med Biol. 2012;39:570–578. doi: 10.1016/j.nucmedbio.2011.10.012. [DOI] [PubMed] [Google Scholar]
  • [87].Mizrahi R, Rusjan PM, Kennedy J, Pollock B, Mulsant B, Suridjan I, et al. Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [18F]FEPPA. J Cereb Blood Flow Metab. 2012;32:968–972. doi: 10.1038/jcbfm.2012.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [88].Guo Q, Colasanti A, Owen DR, Onega M, Kamalakaran A, Bennacef I, et al. Quantification of the specific translocator protein signal of 18F-PBR111 in healthy humans: a genetic polymorphism effect on in vivo binding. J Nucl Med. 2013;54:1915–1923. doi: 10.2967/jnumed.113.121020. [DOI] [PubMed] [Google Scholar]
  • [89].Brust P, Deuther-Conrad W, Lehmkuhl K, Jia H, Wünsch B. Molecular imaging of σ1 receptors in vivo: current status and perspectives. Curr Med Chem. 2014;21:35–69. doi: 10.2174/09298673113209990214. [DOI] [PubMed] [Google Scholar]
  • [90].Jansen KL, Faull RL, Storey P, Leslie RA. Loss of sigma binding sites in the CA1 area of the anterior hippocampus in Alzheimer’s disease correlates with CA1 pyramidal cell loss. Brain Res. 1993;623:299–302. doi: 10.1016/0006-8993(93)91441-t. [DOI] [PubMed] [Google Scholar]
  • [91].Weissman AD, Casanova MF, Kleinman JE, London ED, De Souza EB. Selective loss of cerebral cortical sigma, but not PCP binding sites in schizophrenia. Biol Psychiatry. 1991;29:41–54. doi: 10.1016/0006-3223(91)90209-5. [DOI] [PubMed] [Google Scholar]
  • [92].van Waarde A, Rybczynska AA, Ramakrishnan N, Ishiwata K, Elsinga PH, Dierckx RA. Sigma receptors in oncology: therapeutic and diagnostic applications of sigma ligands. Curr Pharm Des. 2010;16:3519–3537. doi: 10.2174/138161210793563365. [DOI] [PubMed] [Google Scholar]
  • [93].Banister SD, Kassiou M. The therapeutic potential of sigma (σ) receptors for the treatment of central nervous system diseases: evaluation of the evidence. Curr Pharm Des. 2012;18:884–901. doi: 10.2174/138161212799436539. [DOI] [PubMed] [Google Scholar]
  • [94].Megalizzi V, Le Mercier M, Decaestecker C. Sigma receptors and their ligands in cancer biology: overview and new perspectives for cancer therapy. Med Res Rev. 2012;32:410–427. doi: 10.1002/med.20218. [DOI] [PubMed] [Google Scholar]
  • [95].Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav Brain Res. 2011;221:555–563. doi: 10.1016/j.bbr.2010.11.058. [DOI] [PubMed] [Google Scholar]
  • [96].Brust P, Deuther-Conrad W. Molecular imaging of α7 nicotinic acetylcholine receptors in vivo: current status and perspectives. In: Bright P, editor. Neuroimaging — Clinical Applications. 2012. pp. 533–558. [Google Scholar]
  • [97].Brust P, Peters D, Deuther-Conrad W. Development of radioligands for the imaging of α7 nicotinic acetylcholine receptors with positron emission tomography. Curr Drug Targets. 2012;13:594–601. doi: 10.2174/138945012800398955. [DOI] [PubMed] [Google Scholar]
  • [98].Kadir A, Almkvist O, Wall A, Langström B, Nordberg A. PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer’s disease. Psychopharmacology. 2006;188:509–520. doi: 10.1007/s00213-006-0447-7. [DOI] [PubMed] [Google Scholar]
  • [99].Papke RL. Biochem Pharmacol. 2014. Merging old and new perspectives on nicotinic acetylcholine receptors. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [100].Moerlein SM. Molecular imaging and the development of new radiopharmaceuticals. In: Kowalsky RJ, Falen SW, editors. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. 2011. p. 741. [Google Scholar]
  • [101].Davenport AP, Russel FD. Radioligand Binding Assays: Theory and Practice. In: Mather SJ, editor. Current Directions in Radiopharmaceutical Research and Development. 1996. pp. 169–179. [Google Scholar]
  • [102].Koeppe RA. A panel discussion on the future of pharmacology and experimental tomography. In: Gjedde A, Hansen SB, Knudsen GM, Paulson OB, editors. Physiological Imaging of the Brain with PET. 2001. p. 402. [Google Scholar]
  • [103].Hurst R, Rollema H, Bertrand D. Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther. 2013;137:22–54. doi: 10.1016/j.pharmthera.2012.08.012. [DOI] [PubMed] [Google Scholar]
  • [104].Lendvai B, Kassai F, Szajli A, Nemethy Z. alpha7 Nicotinic acetylcholine receptors and their role in cognition. Brain Res Bull. 2013;93:86–96. doi: 10.1016/j.brainresbull.2012.11.003. [DOI] [PubMed] [Google Scholar]
  • [105].Sorger D, Scheunemann M, Vercouillie J, Grossmann U, Fischer S, Hiller A, et al. Neuroimaging of the vesicular acetylcholine transporter by a novel 4-[18F]fluoro-benzoyl derivative of 7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydrobenzo[1,4]oxazines. Nucl Med Biol. 2009;36:17–27. doi: 10.1016/j.nucmedbio.2008.10.006. [DOI] [PubMed] [Google Scholar]
  • [106].Giboureau N, Som IM, Boucher-Arnold A, Guilloteau D, Kassiou M. PET radioligands for the vesicular acetylcholine transporter (VAChT) Curr Top Med Chem. 2010;10:1569–1583. doi: 10.2174/156802610793176846. [DOI] [PubMed] [Google Scholar]
  • [107].Fujita M, Innis RB. In vivo molecular imaging: ligand development and research applications. In: Borroni E, Kupfer DJ, editors. Neuropsychopharmacology: The Fifth Generation of Progress. New York: Raven Press Ltd; 2002. pp. 411–425. [Google Scholar]
  • [108].Blower PJ. Microautoradiography. In: Mather SJ, editor. Current Directions in Radiopharmaceutical Research and Development. 1996. pp. 219–232. [Google Scholar]
  • [109].Lapchak PA, Araujo DM, Hefti F. Effects of chronic nerve growth factor treatment on hippocampal [3H]cytisine/nicotinic binding sites and presynaptic nicotinic receptor function following fimbrial transections. Neuroscience. 1994;60:293–298. doi: 10.1016/0306-4522(94)90243-7. [DOI] [PubMed] [Google Scholar]
  • [110].Rubboli F, Court JA, Sala C, Morris C, Perry E, Clementi F. Distribution of neuronal nicotinic receptor subunits in human brain. Neurochem Int. 1994;25:69–71. doi: 10.1016/0197-0186(94)90055-8. [DOI] [PubMed] [Google Scholar]
  • [111].Baddick CG, Marks MJ. An autoradiographic survey of mouse brain nicotinic acetylcholine receptors defined by null mutants. Biochem Pharmacol. 2011;82:828–841. doi: 10.1016/j.bcp.2011.04.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [112].Morley BJ, Kemp GE, Salvaterra P. α-Bungarotoxin binding sites in the CNS. Life Sci. 1979;24:859–872. doi: 10.1016/0024-3205(79)90335-7. [DOI] [PubMed] [Google Scholar]
  • [113].Whiteaker P, Davies AR, Marks MJ, Blagbrough IS, Potter BV, Wolstenholme AJ, et al. An autoradiographic study of the distribution of binding sites for the novel α7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain. Eur J Neurosci. 1999;11:2689–2696. doi: 10.1046/j.1460-9568.1999.00685.x. [DOI] [PubMed] [Google Scholar]
  • [114].Deuther-Conrad W, Fischer S, Hiller A, Nielsen EO, Timmermann DB, Steinbach J, et al. Molecular imaging of α7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [18F]NS10743. Eur J Nucl Med Mol Imaging. 2009;36:791–800. doi: 10.1007/s00259-008-1031-7. [DOI] [PubMed] [Google Scholar]
  • [115].Daly JW. Thirty years of discovering arthropod alkaloids in amphibian skin. J Nat Prod. 1998;61:162–172. doi: 10.1021/np970460e. [DOI] [PubMed] [Google Scholar]
  • [116].Avalos M, Parker MJ, Maddox FN, Carroll FI, Luetje CW. Effects of pyridine ring substitutions on affinity, efficacy, and subtype selectivity of neuronal nicotinic receptor agonist epibatidine. J Pharmacol Exp Ther. 2002;302:1246–1252. doi: 10.1124/jpet.102.035899. [DOI] [PubMed] [Google Scholar]
  • [117].Deuther-Conrad W, Patt JT, Feuerbach D, Wegner F, Brust P, Steinbach J. Norchloro-fluoro-homoepibatidine: specificity to neuronal nicotinic acetylcholine receptor subtypes in vitro. Farmaco. 2004;59:785–792. doi: 10.1016/j.farmac.2004.07.004. [DOI] [PubMed] [Google Scholar]
  • [118].Deuther-Conrad W, Patt JT, Lockman PR, Allen DD, Patt M, Schildan A, et al. Norchloro-fluoro-homoepibatidine (NCFHEB) — A promising radioligand for neuroimaging nicotinic acetylcholine receptors with PET. Eur Neuropsychopharmacol. 2008;18:222–229. doi: 10.1016/j.euroneuro.2007.07.002. [DOI] [PubMed] [Google Scholar]
  • [119].Smits R, Fischer S, Hiller A, Deuther-Conrad W, Wenzel B, Patt M, et al. Synthesis and biological evaluation of both enantiomers of [18F]flubatine, promising radiotracers with fast kinetics for the imaging of α4β2-nicotinic acetylcholine receptors. Bioorg Med Chem. 2014;22:804–812. doi: 10.1016/j.bmc.2013.12.011. [DOI] [PubMed] [Google Scholar]
  • [120].Patt JT, Spang JE, Westera G, Buck A, Schubiger PA. Synthesis and in Vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers. Nucl Med Biol. 1999;26:165–173. doi: 10.1016/s0969-8051(98)00084-5. [DOI] [PubMed] [Google Scholar]
  • [121].Molina PE, Ding YS, Carroll FI, Liang F, Volkow ND, Pappas N, et al. Fluoro-norchloroepibatidine: preclinical assessment of acute toxicity. Nucl Med Biol. 1997;24:743–747. doi: 10.1016/s0969-8051(97)00120-0. [DOI] [PubMed] [Google Scholar]
  • [122].Gandiha A, Marshall IG. The effects of 2-(4-phenylpiperidino)-cyclohexanol (AH5183) on the acetylcholine content of, and output from, the chick biventer cervicis muscle preparation. Int J Neurosci. 1973;5:191–196. doi: 10.3109/00207457309149474. [DOI] [PubMed] [Google Scholar]
  • [123].Prior C, Marshall IG, Parsons SM. The pharmacology of vesamicol: an inhibitor of the vesicular acetylcholine transporter. Gen Pharmacol. 1992;23:1017–1022. doi: 10.1016/0306-3623(92)90280-w. [DOI] [PubMed] [Google Scholar]
  • [124].Hicks BW, Rogers GA, Parsons SM. Purification and characterization of a nonvesicular vesamicol-binding protein from electric organ and demonstration of a related protein in mammalian brain. J Neurochem. 1991;57:509–519. doi: 10.1111/j.1471-4159.1991.tb03780.x. [DOI] [PubMed] [Google Scholar]
  • [125].Kovac M, Mavel S, Deuther-Conrad W, Meheux N, Glockner J, Wenzel B, et al. 3D QSAR study, synthesis, and in vitro evaluation of (+)-5-FBVM as potential PET radioligand for the vesicular acetylcholine transporter (VAChT) Bioorg Med Chem. 2010;18:7659–7667. doi: 10.1016/j.bmc.2010.08.028. [DOI] [PubMed] [Google Scholar]
  • [126].Mulholland GK, Jung YW, Wieland DM, Kilbourn MR, Kuhl DE. Synthesis of [18F] fluoroethoxy-benzovesamicol, a radiotracer for cholinergic neurons. J Labelled Comp Radiopharm. 1993;33:583–591. [Google Scholar]
  • [127].Petrou M, Frey KA, Kilbourn MR, Scott PJ, Raffel DM, Bohnen NI, et al. J Nucl Med. 2014. In vivo imaging of human cholinergic nerve terminals with (-)-5-18F-fluoroethoxybenzovesamicol: biodistribution, dosimetry, and tracer kinetic analyses. [DOI] [PubMed] [Google Scholar]
  • [128].Parent MJ, Bedard MA, Aliaga A, Minuzzi L, Mechawar N, Soucy JP, et al. Cholinergic depletion in Alzheimer’s disease shown by [18F]FEOBV autoradiography. Int J Mol Imaging. 2013;2013:205045. doi: 10.1155/2013/205045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [129].Szymoszek A, Wenzel B, Scheunemann M, Steinbach J, Schüürmann G. First CoMFA characterization of vesamicol analogs as ligands for the vesicular acetylcholine transporter. J Med Chem. 2008;51:2128–2136. doi: 10.1021/jm700961r. [DOI] [PubMed] [Google Scholar]
  • [130].Maier CA, Wünsch B. Novel spiropiperidines as highly potent and subtype selective σ-receptor ligands. Part 1. J Med Chem. 2002;45:438–448. doi: 10.1021/jm010992z. [DOI] [PubMed] [Google Scholar]
  • [131].Maier CA, Wünsch B. Novel s receptor ligands. Part 2. SAR of spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2] benzofuran-1,4′-piperidines] with carbon substituents in position 3. J Med Chem. 2002;45:4923–4930. doi: 10.1021/jm020889p. [DOI] [PubMed] [Google Scholar]
  • [132].Maier CA, Wünsch B. Eur J Org Chem. 2003. Novel s receptor ligands, Part 3: Synthesis and SAR studies of 3-substituted 1′-benzylspiro[[2] benzoxepine-1,4′-piperidines] pp. 714–720. [Google Scholar]
  • [133].Große Maestrup E, Fischer S, Wiese C, Schepmann D, Hiller A, Deuther-Conrad W, et al. Evaluation of spirocyclic 3-(3-fluoropropyl)-2-benzofurans as σ1 receptor ligands for neuroimaging with positron emission tomography. J Med Chem. 2009;52:6062–6072. doi: 10.1021/jm900909e. [DOI] [PubMed] [Google Scholar]
  • [134].Große Maestrup E, Wiese C, Schepmann D, Brust P, Wünsch B. Synthesis, pharmacological activity and structure affinity relationships of spirocyclic σ1 receptor ligands with a (2-fluoroethyl) residue in 3-position. Bioorg Med Chem. 2011;19:393–405. doi: 10.1016/j.bmc.2010.11.013. [DOI] [PubMed] [Google Scholar]
  • [135].Große Maestrup E, Wiese C, Schepmann D, Hiller A, Fischer S, Scheunemann M, et al. Synthesis of spirocyclic sigma(1) receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability. Bioorg Med Chem. 2009;17:3630–3641. doi: 10.1016/j.bmc.2009.03.060. [DOI] [PubMed] [Google Scholar]
  • [136].Holl K, Falck E, Köhler J, Schepmann D, Humpf HU, Brust P, et al. Synthesis, characterization, and metabolism studies of fluspidine enantiomers. Chem Med Chem. 2013;8:2047–2056. doi: 10.1002/cmdc.201300322. [DOI] [PubMed] [Google Scholar]
  • [137].Maisonial A, Grosse Maestrup E, Fischer S, Hiller A, Scheunemann M, Wiese C, et al. A 18F-labeled fluorobutyl-substituted spirocyclic piperidine derivative as a selective radioligand for PET Imaging of σ1 receptors. Chem Med Chem. 2011;6:1401–1410. doi: 10.1002/cmdc.201100108. [DOI] [PubMed] [Google Scholar]
  • [138].Maisonial A, Grosse Maestrup E, Wiese C, Hiller A, Schepmann D, Fischer S, et al. Synthesis, radiofluorination and pharmacological evaluation of a fluoromethyl spirocyclic PET tracer for central σ1 receptors and comparison with fluoroalkyl homologs. Bioorg Med Chem. 2012;20:257–269. doi: 10.1016/j.bmc.2011.11.002. [DOI] [PubMed] [Google Scholar]
  • [139].Fischer S, Wiese C, Grosse Maestrup E, Hiller A, Deuther-Conrad W, Scheunemann M, et al. Molecular imaging of sigma receptors: synthesis and evaluation of the potent σ1 selective radioligand [18F]fluspidine. Eur J Nucl Med Mol Imaging. 2011;38:540–551. doi: 10.1007/s00259-010-1658-z. [DOI] [PubMed] [Google Scholar]
  • [140].Bickel U. How to measure drug transport across the blood-brain barrier. NeuroRx. 2005;2:15–26. doi: 10.1602/neurorx.2.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [141].Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32:1959–1972. doi: 10.1038/jcbfm.2012.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [142].Kessler RM, Ansari MS, de Paulis T, Schmidt DE, Clanton JA, Smith HE, et al. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides. J Nucl Med. 1991;32:1593–1600. [PubMed] [Google Scholar]
  • [143].Tsuji A. Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems. NeuroRx. 2005;2:54–62. doi: 10.1602/neurorx.2.1.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [144].Ecker GF, Noe CR. In silico prediction models for blood-brain barrier permeation. Curr Med Chem. 2004;11:1617–1628. doi: 10.2174/0929867043365071. [DOI] [PubMed] [Google Scholar]
  • [145].Gouverneur V, Müller K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications. Singapore: World Scientific Publishing; 2012. [Google Scholar]
  • [146].Tressaud A, Haufe G, editors. Fluorine and Health, Molecular Imaging, Biomedical Materials and Pharmaceuticals. 2008. [Google Scholar]
  • [147].Alauddin MM. Positron emission tomography (PET) imaging with 18F-based radiotracers. Am J Nucl Med Mol Imaging. 2012;2:55–76. [PMC free article] [PubMed] [Google Scholar]
  • [148].Ross TL, Wester HJ. 18F: Labeling chemistry and labeled compounds. In: Vértes A, Nagy S, Klencsár Z, Lovas R, Rösch F, editors. Handbook of Nuclear Chemistry: Radiochemistry and Radiopharmaceutical Chemistry in Life Sciences. 2nd Ed. 2011. pp. 2021–2071. [Google Scholar]
  • [149].Schubiger PA, Lehmann L, Friebe M. Springer. 2007. PET Chemistry: The Driving Force in Molecular Imaging. [Google Scholar]
  • [150].Bergman J, Solin O. Fluorine-18-labeled fluorine gas for synthesis of tracer molecules. Nucl Med Biol. 1997;24:677–683. doi: 10.1016/s0969-8051(97)00078-4. [DOI] [PubMed] [Google Scholar]
  • [151].Forsback S, Marjamäki P, Eskola O, Bergman J, Rokka J, Grönroos T, et al. [18F]CFT synthesis and binding to monoamine transporters in rats. EJNMMI Res. 2012;2:3. doi: 10.1186/2191-219X-2-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [152].Ermisch A, Brust P, Kretzschmar R, Rühle HJ. Peptides and Blood-Brain Barrier Transport. Physiol Rev. 1993;73:489–527. doi: 10.1152/physrev.1993.73.3.489. [DOI] [PubMed] [Google Scholar]
  • [153].Coenen HH, Hamacher K, Schüller M, Stöcklin G, Klatte B, Knöchel A. Process for the preparation of fluorine-18 labelled compounds by nucleophilic exchange. 1985. [Google Scholar]
  • [154].Coenen HH, Colosimo M, Schüller M, Stöcklin G. Preparation of n.c.a. [18F]CH2BrF via aminopolyether supported nucleophilic substitution. J Labelled Compd Radiopharm. 1986;23:587–595. [Google Scholar]
  • [155].Roeda D, Dolle F. Aliphatic nucleophilic radiofluorination. Curr Radiopharm. 2010;3:81–108. [Google Scholar]
  • [156].Cai LS, Lu SY, Pike VW. European J Org Chem. 2008. Chemistry with [18F]fluoride ion; pp. 2853–2873. [Google Scholar]
  • [157].Hoepping A, Scheunemann M, Fischer S, Deuther-Conrad W, Hiller A, Wegner F, et al. Radiosynthesis and biological evaluation of an 18F-labeled derivative of the novel pyrazolopyrimidine sedative-hypnotic agent indiplon. Nucl Med Biol. 2007;34:559–570. doi: 10.1016/j.nucmedbio.2007.03.011. [DOI] [PubMed] [Google Scholar]
  • [158].Deuther-Conrad W, Fischer S, Scheunemann M, Hiller A, Diekers M, Friemel A, et al. GABAA receptor specific pyrazolopyrimidines as potential imaging agents: In vivo characteristics of a new 18F-labelled Indiplon derivative. Curr Radiopharm. 2009;2:24–31. [Google Scholar]
  • [159].Fischer S, Hiller A, Scheunemann M, Deuther-Conrad W, Hoepping A, Diekers M, et al. Radiosynthesis of novel 18F-labelled derivatives of indiplon as potential GABAA receptor imaging tracers for PET. J Labelled Comp Radiopharm. 2008;51:123–131. [Google Scholar]
  • [160].Schirrmacher R, Bradtmöller G, Schirrmacher E, Thews O, Tillmanns J, Siessmeier T, et al. 18F-labeling of peptides by means of an organosilicon-based fluoride acceptor. Angew Chem Int Ed Engl. 2006;45:6047–6050. doi: 10.1002/anie.200600795. [DOI] [PubMed] [Google Scholar]
  • [161].Römer J, Füchtner F, Steinbach J, Kasch H. Automated synthesis of 16α-[18F]fluoroestradiol-3,17β-disulphamate. Appl Radiat Isot. 2001;55:631–639. doi: 10.1016/s0969-8043(00)00339-0. [DOI] [PubMed] [Google Scholar]
  • [162].Ermert J, Coenen HH. Nucleophilic 18F-fluorination of complex molecules in activated carbocyclic aromatic position. Curr Radiopharm. 2010;3:109–126. [Google Scholar]
  • [163].Fischer S, Hiller A, Smits R, Hoepping A, Funke U, Wenzel B, et al. Radiosynthesis of racemic and enantiomerically pure (-)-[18F]flubatine-A promising PET radiotracer for neuroimaging of α4β2 nicotinic acetylcholine receptors. Appl Radiat Isot. 2013;74C:128–136. doi: 10.1016/j.apradiso.2013.01.002. [DOI] [PubMed] [Google Scholar]
  • [164].Patt JT, Deuther-Conrad W, Wohlfarth K, Feuerbach D, Brust P, Steinbach J. Norchloro-fluoro-homoepibatidine: 18F-labelling and evaluation of affinity and selectivity at neuronal nicotinic acetylcholine receptors. J Labelled Compd Radiopharm. 2003;46(S1):168. [Google Scholar]
  • [165].Patt M, Schildan A, Habermann B, Fischer S, Hiller A, Deuther-Conrad W, et al. Fully automated radiosynthesis of both enantiomers of [18F]Flubatine under GMP conditions for human application. Appl Radiat Isot. 2013;80:7–11. doi: 10.1016/j.apradiso.2013.05.009. [DOI] [PubMed] [Google Scholar]
  • [166].Hockley BG, Stewart MN, Sherman P, Quesada C, Kilbourn MR, Albin RL, et al. (-)-[18F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use. J Labelled Comp Radiopharm. 2013;56:595–599. doi: 10.1002/jlcr.3069. [DOI] [PubMed] [Google Scholar]
  • [167].Rühl T, Deuther-Conrad W, Fischer S, Günther R, Hennig L, Krautscheid H, et al. Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation. Org Med Chem Lett. 2012;2:32. doi: 10.1186/2191-2858-2-32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [168].Teodoro R, Moldovan RP, Lueg C, Günther R, Donat CK, Ludwig FA, et al. Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors. Org Med Chem Lett. 2013;3:11. doi: 10.1186/2191-2858-3-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [169].Löser R, Fischer S, Hiller A, Köckerling M, Funke U, Maisonial A, et al. Use of 3-[18F]fluoropropanesulfonyl chloride as a prosthetic agent for the radiolabelling of amines: Investigation of precursor molecules, labelling conditions and enzymatic stability of the corresponding sulfonamides. Beilstein J Org Chem. 2013;9:1002–1011. doi: 10.3762/bjoc.9.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [170].Wüst F, Köhler L, Berndt M, Pietzsch J. Systematic comparison of two novel, thiol-reactive prosthetic groups for 18F labeling of peptides and proteins with the acylation agent succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) Amino Acids. 2009;36:283–295. doi: 10.1007/s00726-008-0065-2. [DOI] [PubMed] [Google Scholar]
  • [171].Serdons K, Verbruggen A, Bormans GM. Developing new molecular imaging probes for PET. Methods. 2009;48:104–111. doi: 10.1016/j.ymeth.2009.03.010. [DOI] [PubMed] [Google Scholar]
  • [172].Pretze M, Kuchar M, Bergmann R, Steinbach J, Pietzsch J, Mamat C. An efficient bioorthogonal strategy using CuAAC click chemistry for radiofluorinations of SNEW peptides and the role of copper depletion. Chem Med Chem. 2013;8:935–945. doi: 10.1002/cmdc.201300053. [DOI] [PubMed] [Google Scholar]
  • [173].Pretze M, Pietzsch D, Mamat C. Recent trends in bioorthogonal click-radiolabeling reactions using fluorine-18. Molecules. 2013;18:8618–8665. doi: 10.3390/molecules18078618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [174].Ramenda T, Kniess T, Bergmann R, Steinbach J, Wüst F. Chem Commun (Camb) 2009. Radiolabelling of proteins with fluorine-18 via click chemistry; pp. 7521–7523. [DOI] [PubMed] [Google Scholar]
  • [175].Ramenda T, Steinbach J, Wüst F. 4-[18F]Fluoro-N-methyl-N-(propyl-2-yn-1-yl)benzenesulfonamide ([18F]F-SA): a versatile building block for labeling of peptides, proteins and oligonucleotides with fluorine-18 via Cu(I)-mediated click chemistry. Amino Acids. 2013;44:1167–1180. doi: 10.1007/s00726-012-1450-4. [DOI] [PubMed] [Google Scholar]
  • [176].Kniess T, Laube M, Bergmann R, Sehn F, Graf F, Steinbach J, et al. Radiosynthesis of a 18F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo. Bioorg Med Chem. 2012;20:3410–3421. doi: 10.1016/j.bmc.2012.04.022. [DOI] [PubMed] [Google Scholar]
  • [177].Funke U, Fischer S, Hiller A, Scheunemann M, Deuther-Conrad W, Brust P, et al. 3-(4-(6-Fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)-1H-indol e-5-carbonitriles for SERT imaging: chemical synthesis, evaluation in vitro and radiofluorination. Bioorg Med Chem Lett. 2008;18:4727–4730. doi: 10.1016/j.bmcl.2008.06.077. [DOI] [PubMed] [Google Scholar]
  • [178].Funke U, Schwan G, Maisonial A, Scheunemann M, Deuther-Conrad W, Fischer S, et al. Radiosynthesis and radiotracer properties of a 7-(2-[18F]fluoroethoxy)-6-methoxypyrrolidinylquinazoline for imaging of phosphodiesterase 10A with PET. Pharmaceuticals (Basel) 2012;5:169–188. doi: 10.3390/ph5020169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [179].Sorger D, Scheunemann M, Grossmann U, Fischer S, Vercouille J, Hiller A, et al. A new 18F-labeled fluoroacetylmorpholino derivative of vesamicol for neuroimaging of the vesicular acetylcholine transporter. Nucl Med Biol. 2008;35:185–195. doi: 10.1016/j.nucmedbio.2007.10.004. [DOI] [PubMed] [Google Scholar]
  • [180].Hoepping A, Scheunemann M, Fischer S, Deuther-Conrad W, Hiller A, Wegner F, et al. Radiosynthesis and biological evaluation of an 18F-labeled derivative of the novel pyrazolopyrimidine sedative-hypnotic agent indiplon. Nucl Med Biol. 2007;34:559–570. doi: 10.1016/j.nucmedbio.2007.03.011. [DOI] [PubMed] [Google Scholar]
  • [181].Donat CK, Schuhmann MU, Voigt C, Nieber K, Deuther-Conrad W, Brust P. Time-dependent alterations of cholinergic markers after experimental traumatic brain injury. Brain Res. 2008;1246:167–177. doi: 10.1016/j.brainres.2008.09.059. [DOI] [PubMed] [Google Scholar]
  • [182].Perry DC, Kellar KJ. [3H]epibatidine labels nicotinic receptors in rat brain: an autoradiographic study. J Pharmacol Exp Ther. 1995;275:1030–1034. [PubMed] [Google Scholar]
  • [183].Vaupel DB, Mukhin AG, Kimes AS, Horti AG, Koren AO, London ED. In vivo studies with [125I]5-I-A-85380, a nicotinic acetylcholine receptor radioligand. Neuroreport. 1998;9:2311–2317. doi: 10.1097/00001756-199807130-00030. [DOI] [PubMed] [Google Scholar]
  • [184].Davies AR, Hardick DJ, Blagbrough IS, Potter BV, Wolstenholme AJ, Wonnacott S. Characterisation of the binding of [3H]methyllycaconitine: a new radioligand for labelling α7-type neuronal nicotinic acetylcholine receptors. Neuropharmacology. 1999;38:679–690. doi: 10.1016/s0028-3908(98)00221-4. [DOI] [PubMed] [Google Scholar]
  • [185].No-authors-listed. Indiplon. Indiplon modified-release, indiplon MR, NBI 34060, NBI 34060 modified-release, NBI 34060 MR. Drugs R D 2002, 3: 197–199. [DOI] [PubMed]
  • [186].Hoepping A, Diekers M, Deuther-Conrad W, Scheunemann M, Fischer S, Hiller A, et al. Synthesis of fluorine substituted pyrazolopyrimidines as potential leads for the development of PET-imaging agents for the GABAA receptors. Bioorg Med Chem. 2008;16:1184–1194. doi: 10.1016/j.bmc.2007.10.079. [DOI] [PubMed] [Google Scholar]
  • [187].Brust P, Scheffel U, Szabo Z. Radioligands for the study of the 5-HT transporter in vivo. IDrugs. 1999;2:129–145. [PubMed] [Google Scholar]
  • [188].Kretzschmar M, Brust P, Zessin J, Cumming P, Bergmann R, Johannsen B. Autoradiographic imaging of the serotonin transporter in the brain of rats and pigs using S-([18F] Fluoromethyl)-(+)-McN5652. Eur Neuropsychopharmacol. 2003;13:387–397. doi: 10.1016/s0924-977x(03)00039-7. [DOI] [PubMed] [Google Scholar]
  • [189].Kung MP, Stevenson DA, Plössl K, Meegalla SK, Beckwith A, Essman WD, et al. [99mTc]TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent. European J Nucl Med. 1997;24:372–380. doi: 10.1007/BF00881808. [DOI] [PubMed] [Google Scholar]
  • [190].Kung HF, Kung MP, Wey SP, Lin KJ, Yen TC. Clinical acceptance of a molecular imaging agent: a long march with [Tc-99m]TRODAT. Nucl Med Biol. 2007;34:787–789. doi: 10.1016/j.nucmedbio.2007.03.010. [DOI] [PubMed] [Google Scholar]
  • [191].Tan PZ, Baldwin RM, Van Dyck CH, Al-Tikriti M, Roth B, Khan N, et al. Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol. 1999;26:601–608. doi: 10.1016/s0969-8051(99)00022-0. [DOI] [PubMed] [Google Scholar]
  • [192].van Dyck CH, Tan PZ, Baldwin RM, Amici LA, Garg PK, Ng CK, 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. [PubMed] [Google Scholar]
  • [193].Liptrot M, Adams KH, Martiny L, Pinborg LH, Lonsdale MN, Olsen NV, et al. Cluster analysis in kinetic modelling of the brain: a noninvasive alternative to arterial sampling. Neuroimage. 2004;21:483–493. doi: 10.1016/j.neuroimage.2003.09.058. [DOI] [PubMed] [Google Scholar]
  • [194].Bergström KA, Halldin C, Kuikka JT, Swahn CG, Tiihonen J, Hiltunen J, et al. Lipophilic metabolite of [123I]β-CIT in human plasma may obstruct quantitation of the dopamine transporter. Synapse. 1995;19:297–300. doi: 10.1002/syn.890190407. [DOI] [PubMed] [Google Scholar]
  • [195].Lundkvist C, Halldin C, Swahn CG, Ginovart N, Farde L. Different brain radioactivity curves in a PET study with [11C] β-CIT labelled in two different positions. Nucl Med Biol. 1999;26:343–350. doi: 10.1016/s0969-8051(98)00111-5. [DOI] [PubMed] [Google Scholar]
  • [196].Zoghbi SS, Shetty HU, Ichise M, Fujita M, Imaizumi M, Liow JS, et al. PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements. J Nucl Med. 2006;47:520–527. [PubMed] [Google Scholar]
  • [197].Shetty HU, Zoghbi SS, Liow JS, Ichise M, Hong J, Musachio JL, et al. Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I. Eur J Nucl Med Mol Imaging. 2007;34:667–678. doi: 10.1007/s00259-006-0277-1. [DOI] [PubMed] [Google Scholar]
  • [198].Peyronneau MA, Saba W, Dolle F, Goutal S, Coulon C, Bottlaender M, et al. Difficulties in dopamine transporter radioligand PET analysis: the example of LBT-999 using [18F] and [11C] labelling: part II: Metabolism studies. Nucl Med Biol. 2012;39:347–359. doi: 10.1016/j.nucmedbio.2011.09.006. [DOI] [PubMed] [Google Scholar]
  • [199].Bergström KA, Halldin C, Hall H, Lundkvist C, Ginovart N, Swahn CG, et al. In vitro and in vivo characterisation of nor-β-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain. European J Nucl Med. 1997;24:596–601. doi: 10.1007/BF00841395. [DOI] [PubMed] [Google Scholar]
  • [200].Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol. 2001;14:611–650. doi: 10.1021/tx0002583. [DOI] [PubMed] [Google Scholar]
  • [201].Carroll FI, Blough BE, Nie Z, Kuhar MJ, Howell LL, Navarro HA. Synthesis and monoamine transporter binding properties of 3beta-(3′,4′-disubstituted phenyl)tropane-2beta-carboxylic acid methyl esters. J Med Chem. 2005;48:2767–2771. doi: 10.1021/jm040185a. [DOI] [PubMed] [Google Scholar]
  • [202].Mori T, Sun LQ, Kobayashi M, Kiyono Y, Okazawa H, Furukawa T, et al. Preparation and evaluation of ethyl [18F] fluoroacetate as a proradiotracer of [18F]fluoroacetate for the measurement of glial metabolism by PET. Nucl Med Biol. 2009;36:155–162. doi: 10.1016/j.nucmedbio.2008.11.006. [DOI] [PubMed] [Google Scholar]
  • [203].Dienel GA, Popp D, Drew PD, Ball K, Krisht A, Cruz NF. Preferential labeling of glial and meningial brain tumors with [2-14C]acetate. J Nucl Med. 2001;42:1243–1250. [PubMed] [Google Scholar]
  • [204].Lear JL, Ackermann RF. Evaluation of radiolabeled acetate and fluoroacetate as potential tracers of cerebral oxidative metabolism. Metab Brain Dis. 1990;5:45–56. doi: 10.1007/BF00996977. [DOI] [PubMed] [Google Scholar]
  • [205].Davson H, Segal MB. Physiology of the CSF and Blood-Brain Barriers. Boca Raton, USA: CRC Press; 1996. [Google Scholar]
  • [206].Rogers GA, Stone-Elander S, Ingvar M, Eriksson L, Parsons SM, Widen L. 18F-labelled vesamicol derivatives: syntheses and preliminary in vivo small animal positron emission tomography evaluation. Nucl Med Biol. 1994;21:219–230. doi: 10.1016/0969-8051(94)90012-4. [DOI] [PubMed] [Google Scholar]
  • [207].Tu LQ, Wright PF, Rix CJ, Ahokas JT. Is fluoroacetate-specific defluorinase a glutathione S-transferase? Comp Biochem Physiol C Toxicol Pharmacol. 2006;143:59–66. doi: 10.1016/j.cbpc.2005.12.003. [DOI] [PubMed] [Google Scholar]
  • [208].Johnson JA, el Barbary A, Kornguth SE, Brugge JF, Siegel FL. Glutathione S-transferase isoenzymes in rat brain neurons and glia. J Neurosci. 1993;13:2013–2023. doi: 10.1523/JNEUROSCI.13-05-02013.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [209].Brust P, Hinz R, Kuwabara H, Hesse S, Zessin J, Pawelke B, et al. In vivo measurement of the serotonin transporter with (S)-([18F]fluoromethyl)-(+)-McN5652. Neuropsychopharmacology. 2003;28:2010–2019. doi: 10.1038/sj.npp.1300281. [DOI] [PubMed] [Google Scholar]
  • [210].Hesse S, Brust P, Mäding P, Becker GA, Patt M, Seese A, et al. Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans. Eur J Nucl Med Mol Imaging. 2012;39:1001–1011. doi: 10.1007/s00259-012-2078-z. [DOI] [PubMed] [Google Scholar]
  • [211].Szabo Z, Scheffel U, Mathews WB, Ravert HT, Szabo K, Kraut M, et al. Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand. J Cereb Blood Flow Metab. 1999;19:967–981. doi: 10.1097/00004647-199909000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [212].Brust P, Patt JT, Deuther-Conrad W, Becker G, Patt M, Schildan A, et al. In vivo measurement of nicotinic acetylcholine receptors with [18F]norchloro-fluoro-homoepibatidine. Synapse. 2008;62:205–218. doi: 10.1002/syn.20480. [DOI] [PubMed] [Google Scholar]
  • [213].Patt M, Becker GA, Grossmann U, Habermann B, Schildan A, Wilke S, et al. Nucl Med Biol. 2014. Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[18F]flubatine in humans. [DOI] [PubMed] [Google Scholar]
  • [214].Becker GA, Wilke S, Schönknecht P, Patt M, Luthardt J, Hesse S, et al. Comparison of (-)-[18F]-flubatine and 2-[18F] FA-85380 binding to nicotinic alpha4beta2 acetylcholine receptors in human brains. Eur J Nucl Med Mol Imaging. 2013;40(Suppl.2):S271. [Google Scholar]
  • [215].Fasinu P, Bouic PJ, Rosenkranz B. Liver-based in vitro technologies for drug biotransformation studies — a review. Curr Drug Metab. 2012;13:215–224. doi: 10.2174/138920012798918426. [DOI] [PubMed] [Google Scholar]
  • [216].Davydov DR. Microsomal monooxygenase as a multienzyme system: the role of P450-P450 interactions. Expert Opin Drug Metab Toxicol. 2011;7:543–558. doi: 10.1517/17425255.2011.562194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [217].Stabin MG. Springer. 2008. Fundamentals of Nuclear Medicine Dosimetry. [Google Scholar]
  • [218].van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J Drug Target. 1998;6:151–165. doi: 10.3109/10611869808997889. [DOI] [PubMed] [Google Scholar]
  • [219].Ball K, Bouzom F, Scherrmann JM, Walther B, Decleves X. Physiologically based pharmacokinetic modelling of drug penetration across the blood-brain barrier-towards a mechanistic IVIVE-based approach. AAPS J. 2013;15:913–932. doi: 10.1208/s12248-013-9496-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [220].Shawahna R, Decleves X, Scherrmann JM. Hurdles with using in vitro models to predict human blood-brain barrier drug permeability: a special focus on transporters and metabolizing enzymes. Curr Drug Metab. 2013;14:120–136. [PubMed] [Google Scholar]
  • [221].Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117:333–345. doi: 10.1111/j.1471-4159.2011.07208.x. [DOI] [PubMed] [Google Scholar]
  • [222].Rötering S, Scheunemann M, Fischer S, Hiller A, Peters D, Deuther-Conrad W, et al. Radiosynthesis and first evaluation in mice of [18F]NS14490 for molecular imaging of α7 nicotinic acetylcholine receptors. Bioorg Med Chem. 2013;21:2635–2642. doi: 10.1016/j.bmc.2013.02.018. [DOI] [PubMed] [Google Scholar]
  • [223].Syvänen S, Lindhe O, Palner M, Kornum BR, Rahman O, Langström B, et al. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos. 2009;37:635–643. doi: 10.1124/dmd.108.024745. [DOI] [PubMed] [Google Scholar]
  • [224].Wagner HN, Jr., Burns HD, Dannals RF, Wong DF, Langström B, Duelfer T, et al. Imaging dopamine receptors in the human brain by positron tomography. Science. 1983;221:1264–1266. doi: 10.1126/science.6604315. [DOI] [PubMed] [Google Scholar]
  • [225].Ehrin E, Farde L, de Paulis T, Eriksson L, Greitz T, Johnström P, et al. Preparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: preliminary PET studies of cerebral dopamine receptors in the monkey. Int J Appl Radiat Isot. 1985;36:269–273. doi: 10.1016/0020-708x(85)90083-3. [DOI] [PubMed] [Google Scholar]
  • [226].Chan GL, Holden JE, Stoessl AJ, Doudet DJ, Wang Y, Dobko T, et al. Reproducibility of the distribution of carbon-11-SCH 23390, a dopamine D1 receptor tracer, in normal subjects. J Nucl Med. 1998;39:792–797. [PubMed] [Google Scholar]
  • [227].Parsey RV, Arango V, Olvet DM, Oquendo MA, Van Heertum RL, John Mann J. Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography. J Cereb Blood Flow Metab. 2005;25:785–793. doi: 10.1038/sj.jcbfm.9600072. [DOI] [PubMed] [Google Scholar]
  • [228].Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J, et al. Multicompartmental study of F-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography. Eur J Nucl Med. 1994;21:937–946. doi: 10.1007/BF00238117. [DOI] [PubMed] [Google Scholar]
  • [229].Itoh T, Tanaka M, Kobayashi K, Suzuki K, Inoue O. Binding kinetics of 11C-N-methyl piperidyl benzilate (11C-NMPB) in a rhesus monkey brain using the cerebellum as a reference region. Ann Nucl Med. 2005;19:499–505. doi: 10.1007/BF02985578. [DOI] [PubMed] [Google Scholar]
  • [230].Deuther-Conrad W, Fischer S, Hiller A, Becker G, Cumming P, Xiong G, et al. Assessment of α7 nicotinic acetylcholine receptor availability in porcine brain with [18F]NS10743. Eur J Nucl Med Mol Imaging. 2011;38:1541–1549. doi: 10.1007/s00259-011-1808-y. [DOI] [PubMed] [Google Scholar]
  • [231].Flesher JE, Scheffel U, London ED, Frost JJ. In vivo labeling of nicotinic cholinergic receptors in brain with [3H]cytisine. Life Sci. 1994;54:1883–1890. doi: 10.1016/0024-3205(94)90146-5. [DOI] [PubMed] [Google Scholar]
  • [232].Ishiwata K, Kawamura K, Wang WF, Tsukada H, Harada N, Mochizuki H, et al. Evaluation of in vivo selective binding of [11C]doxepin to histamine H1 receptors in five animal species. Nucl Med Biol. 2004;31:493–502. doi: 10.1016/j.nucmedbio.2003.11.005. [DOI] [PubMed] [Google Scholar]
  • [233].Kish SJ, Furukawa Y, Chang LJ, Tong J, Ginovart N, Wilson A, et al. Regional distribution of serotonin transporter protein in postmortem human brain: Is the cerebellum a SERT-free brain region? Nucl Med Biol. 2005;32:123–128. doi: 10.1016/j.nucmedbio.2004.10.001. [DOI] [PubMed] [Google Scholar]
  • [234].Brust P, Hesse S, Müller U, Szabo Z. Neuroimaging of the serotonin transporter — possibilities and pitfalls. Curr Psychiat Rev. 2006;2:111–149. [Google Scholar]
  • [235].Marjamäki P, Zessin J, Eskola O, Grönroos T, Haaparanta M, Bergman J, et al. S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: Evaluation in rats. Synapse. 2003;47:45–53. doi: 10.1002/syn.10150. [DOI] [PubMed] [Google Scholar]
  • [236].Deuther-Conrad W, Maisonial A, Patt M, Stittsworth S, Becker G, Habermann B, et al. Discovery of enantioselective suitability of (R)-(+)- and (S)-(-)-[18F]fluspidine for σ1 receptor imaging. J Label Comp Radiopharm. 2013;56:S55. [Google Scholar]
  • [237].Brust P, Deuther-Conrad W, Becker G, Patt M, Donat CK, Stittsworth S, et al. Distinctive in vivo kinetics of the new sigma1 receptor ligands (R)-(+)- and (S)-(-)-18F-fluspidine in porcine brain. J Nucl Med. 2014;114:137562. doi: 10.2967/jnumed.114.137562. [DOI] [PubMed] [Google Scholar]
  • [238].Leenders KL, Gibbs JM, Frackowiak RS, Lammertsma AA, Jones T. Positron emission tomography of the brain: new possibilities for the investigation of human cerebral pathophysiology. Prog Neurobiol. 1984;23:1–38. doi: 10.1016/0301-0082(84)90010-8. [DOI] [PubMed] [Google Scholar]
  • [239].Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol. 1984;15:217–227. doi: 10.1002/ana.410150302. [DOI] [PubMed] [Google Scholar]
  • [240].Miyoshi S, Mitsuoka K, Nishimura S, Veltkamp SA. InTech. 2011. Radioisotopes in Drug Research and Development: Focus on Positron Emission Tomography. In: Singh N (Ed). Radioisotopes — Applications in Bio-Medical Science; pp. 93–113. [Google Scholar]
  • [241].Yanai K, Ido T, Ishiwata K, Hatazawa J, Watanuki S, Takahashi T, et al. Characteristics of specific in vivo labeling of neuroleptic binding sites with 3-N-[11C]methylspiperone. European J Nucl Med. 1986;11:438–443. doi: 10.1007/BF00261006. [DOI] [PubMed] [Google Scholar]
  • [242].Brust P, Shaya EK, Jeffries KJ, Dannals RF, Ravert HT, Wilson AA, et al. Effects of vasopressin on blood-brain transfer of methionine in dogs. J Neurochem. 1992;59:1421–1429. doi: 10.1111/j.1471-4159.1992.tb08456.x. [DOI] [PubMed] [Google Scholar]
  • [243].Kong FL, Ford RJ, Yang DJ. Managing lymphoma with non-FDG radiotracers: current clinical and preclinical applications. Biomed Res Int. 2013;2013:626910. doi: 10.1155/2013/626910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [244].Prenen GH, Go KG, Paans AM, Zuiderveen F, Vaalburg W, Kamman RL, et al. Positron emission tomographical studies of 1-11C-acetoacetate, 2-18F-fluoro-deoxy-D-glucose, and L-1-11C-tyrosine uptake by cat brain with an experimental lesion. Acta Neurochirurgica. 1989;99:166–172. doi: 10.1007/BF01402328. [DOI] [PubMed] [Google Scholar]
  • [245].Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S. [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats. Synapse. 2003;47:123–133. doi: 10.1002/syn.10155. [DOI] [PubMed] [Google Scholar]
  • [246].Bauer R, Bergmann R, Beyer GJ, Manfrass P, Steinbach J, Kretzschmar M, et al. Investigations of cerebral glucose utilization into the newborn brain: a [18F]-FDG positron emission tomography study using a high resolution multiwire proportional chamber detector device. Exp Pathol. 1991;42:229–233. doi: 10.1016/s0232-1513(11)80072-1. [DOI] [PubMed] [Google Scholar]
  • [247].Sauleau P, Lapouble E, Val-Laillet D, Malbert CH. The pig model in brain imaging and neurosurgery. Animal. 2009;3:1138–1151. doi: 10.1017/S1751731109004649. [DOI] [PubMed] [Google Scholar]
  • [248].Alstrup AKO, Smith DF. PET neuroimaging in pigs. Scand J Lab Anim Sci. 2012;39:25–45. [Google Scholar]
  • [249].Herzog H. PET/MRI: challenges, solutions and perspectives. Z Med Phys. 2012;22:281–298. doi: 10.1016/j.zemedi.2012.07.003. [DOI] [PubMed] [Google Scholar]
  • [250].Herzog H, van den Hoff J. Combined PET/MR systems: an overview and comparison of currently available options. Q J Nucl Med Mol Imaging. 2012;56:247–267. [PubMed] [Google Scholar]
  • [251].Xi W, Tian M, Zhang H. Neurosci Res. 2011. Molecular imaging in neuroscience research with small-animal PET in rodents. [DOI] [PubMed] [Google Scholar]
  • [252].Lancelot S, Zimmer L. Small-animal positron emission tomography as a tool for neuropharmacology. Trends Pharmacol Sci. 2010;31:411–417. doi: 10.1016/j.tips.2010.06.002. [DOI] [PubMed] [Google Scholar]
  • [253].Syvänen S, Labots M, Tagawa Y, Eriksson J, Windhorst AD, Lammertsma AA, et al. Altered GABAA receptor density and unaltered blood-brain barrier transport in a kainate model of epilepsy: an in vivo study using 11C-flumazenil and PET. J Nucl Med. 2012;53:1974–1983. doi: 10.2967/jnumed.112.104588. [DOI] [PubMed] [Google Scholar]
  • [254].Gunn RN, Gunn SR, Turkheimer FE, Aston JA, Cunningham VJ. Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J Cereb Blood Flow Metab. 2002;22:1425–1439. doi: 10.1097/01.wcb.0000045042.03034.42. [DOI] [PubMed] [Google Scholar]
  • [255].Schmidt KC, Turkheimer FE. Kinetic modeling in positron emission tomography. Quarterly J Nucl Med. 2002;46:70–85. [PubMed] [Google Scholar]
  • [256].Laruelle M, Slifstein M, Huang Y. Positron emission tomography: imaging and quantification of neurotransporter availability. Methods. 2002;27:287–299. doi: 10.1016/s1046-2023(02)00085-3. [DOI] [PubMed] [Google Scholar]
  • [257].Watabe H, Ikoma Y, Kimura Y, Naganawa M, Shidahara M. PET kinetic analysis—compartmental model. Ann Nucl Med. 2006;20:583–588. doi: 10.1007/BF02984655. [DOI] [PubMed] [Google Scholar]
  • [258].van den Hoff J. Principles of quantitative positron emission tomography. Amino Acids. 2005;29:341–353. doi: 10.1007/s00726-005-0215-8. [DOI] [PubMed] [Google Scholar]
  • [259].van den Hoff J. Kinetic Modelling. In: Kiessling F, Pichler BJ, editors. Small Animal Imaging: Basics and Practical Guide. 2010. pp. 387–404. [Google Scholar]
  • [260].Brust P, Zessin J, Kuwabara H, Pawelke B, Kretzschmar M, Hinz R, et al. Positron emission tomography imaging of the serotonin transporter in the pig brain using [11C](+)-McN5652 and S-([18F]fluoromethyl)-(+)-McN5652. Synapse. 2003;47:143–151. doi: 10.1002/syn.10163. [DOI] [PubMed] [Google Scholar]
  • [261].Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, et al. Comparison of methods for analysis of clinical C-11 raclopride studies. J Cereb Blood Flow Metab. 1996;16:42–52. doi: 10.1097/00004647-199601000-00005. [DOI] [PubMed] [Google Scholar]
  • [262].Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4:153–158. doi: 10.1006/nimg.1996.0066. [DOI] [PubMed] [Google Scholar]
  • [263].Wang G, Qi J. Direct estimation of kinetic parametric images for dynamic PET. Theranostics. 2013;3:802–815. doi: 10.7150/thno.5130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [264].Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3:1–7. doi: 10.1038/jcbfm.1983.1. [DOI] [PubMed] [Google Scholar]
  • [265].Patlak CS, Blasberg RG. Graphical evaluation of bloodto-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985;5:584–590. doi: 10.1038/jcbfm.1985.87. [DOI] [PubMed] [Google Scholar]
  • [266].Gjedde A. High-and low-affinity transport of D-glucose from blood to brain. J Neurochem. 1981;36:1463–1471. doi: 10.1111/j.1471-4159.1981.tb00587.x. [DOI] [PubMed] [Google Scholar]
  • [267].Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, 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. doi: 10.1038/jcbfm.1990.127. [DOI] [PubMed] [Google Scholar]
  • [268].Wang JZ, Qiu P, Liu RKJ, Szabo Z. Model-Based receptor quantization analysis for PET parametric imaging. Conf Proc IEEE Eng Med Biol Soc. 2005;6:5908–5911. doi: 10.1109/IEMBS.2005.1615835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [269].Dennan S, Decristoforo Ce. European Association of Nuclear Medicine. 2008. The Radiopharmacy. A Technologist’s Guide. [Google Scholar]
  • [270].Elsinga P, Todde S, Penuelas I, Meyer G, Farstad B, Faivre-Chauvet A, et al. Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals. Eur J Nucl Med Mol Imaging. 2010;37:1049–1062. doi: 10.1007/s00259-010-1407-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [271].Verbruggen A, Coenen HH, Deverre JR, Guilloteau D, Langstrom B, Salvadori PA, et al. Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU. Eur J Nucl Med Mol Imaging. 2008;35:2144–2151. doi: 10.1007/s00259-008-0853-7. [DOI] [PubMed] [Google Scholar]
  • [272].Zessin J, Eskola O, Steinbach J, Bergman J, Marjamäki P, Brust P, et al. Synthesis and first biological evaluation of the [18F]fluormethyl-analog of (+)-MCN5652, a tracer for imaging the serotonin transporter. Nuklearmedizin. 2000;39:A36. [Google Scholar]
  • [273].Petrou M, Koeppe R, Scott P, Bohnen N, Kilbourn M, Frey K. PET imaging of the vesicular acetylcholine transporter. J Nucl Med. 2012;53(Supplement1):290. [Google Scholar]
  • [274].Farde L, Ehrin E, Eriksson L, Greitz T, Hall H, Hedström CG, et al. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci U S A. 1985;82:3863–3867. doi: 10.1073/pnas.82.11.3863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [275].Maziere M, Hantraye P, Prenant C, Sastre J, Comar D. Synthesis of ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine-3-carboxylate (RO 15.1788-11C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography. Int J Appl Radiat Isot. 1984;35:973–976. doi: 10.1016/0020-708x(84)90215-1. [DOI] [PubMed] [Google Scholar]
  • [276].Rowland DJ, Cherry SR. Small-animal preclinical nuclear medicine instrumentation and methodology. Semin Nucl Med. 2008;38:209–222. doi: 10.1053/j.semnuclmed.2008.01.004. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES