Development of PET Radioligands for the Quantitation of Serotonin Receptors in the Human Brain
Pharmacological studies have shown that there are multiple serotonin receptor subtypes, which are classified in at least seven classes. . There has been a lack of subtype selective serotonin receptor radioligands suitable for PET imaging of the human brain. The 5-HT1a receptor is of particular interest as it may be involved in the pathophysiology of several neuropsychiatric disorders, like anxiety, depression and schizophrenia. Recently, a potent and selective 5-HT1a receptor antagonist, WAY-100635 (N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide) was developed. Labelling of WAY-100635 in the methoxy position with 11C [2–3] provided the first radioligand for the delineation of 5-HT1a receptors in the human brain using positron emission tomography (PET) . The descyclohexanecarbonyl analogue ([11C]WAY- 100634) was shown to be a labelled lipophilic metabolite in primates with high affinity to 5-HTlA receptors and high ability to enter the brain, so hampering the quantitation of the uptake of the radioligand in vivo . WAY-100635 has recently been labelled with 11C also in the carbonyl position and examined in the human brain with PET .
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- 2.Pike, V.W., McCarron, J.A., Hume, S.P., Ashworth, S., Opacka-Juffry, J., Osman, S, Lammertsma, A.A., Poole, K.G., Fletcher, A., White, A.C., Cliffe, I.A. (1994) Preclinical development of a radioligand for studies of central 5-HT1A receptors in vivo - [11C]WAY 100635. Med. Chem. Res. 5, 208–227.Google Scholar
- 5.Osman, S., Lundkvist, C., Pike, V.W., Halldin, C., McCarron, J.A., Swahn, C.G., Ginovart, N., Luthra, S.K., Bench, C.J., Grasby, P.M., Wikström, H., Barf, T., Cliffe, I.A., Fletcher, A.C., Farde, L. (1996) Characterization of the metabolites of the 5-HT1A receptor radioligand, [O-methyl- 11C]WAY-100635, in monkey and human plasma - A comparison of the behaviour of an identified radioactive metabolite with parent radioligand using PET. Nucl. Med. Biol. 23, 627–634.PubMedCrossRefGoogle Scholar
- 6.Pike, V.W., McCarron, J.A., Lammertsma, A.A., Osman, S., Hume, S.P., Sargent, P.A., Bench, C.J., Cliffe, I.A., Fletcher, A., Grasby, P.M. (1996) Exquisite delineation of 5-HT IA receptors in human brain with PET and [carbonyl 11C]WAY-100635. Eur. J. Pharmacol. 301, R5–R7.PubMedCrossRefGoogle Scholar
- 7.Kehne, J.H., Baron, B.M., Carr, A.A., Chaney S.F., Elands, J., Feldman, D.J., Frank, R.A., Van Giersbergen, P.L., McCloskey, T.C., Johnson, M.P., McCarty, D.R., Poirot, M., Senyah, Y., Siegel, B.W., Widmaier, C. (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a 5-HT2A receptor antagonist with a favorable CNS safety profile. J. Pharmacol Exp. Ther. 277, 968–981.PubMedGoogle Scholar
- 8.Hall, H., Lundkvist, C., Halldin, C., Farde, L., Pike, V.W., McCarron, J.A., Fletcher, A.C., Cliffe, I.A., Barf, T., Wikström, H., Sedvall, G. (1997) Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635. Brain Res. (in press).Google Scholar
- 9.Osman, S., Lundkvist, C., Pike, V.W., Halldin, C., McCarron, J.A., Swahn, C.G., Farde, L., Ginovart, N., Luthra, S.K., Bench, C.J., Sergeant, P., Cliffe, I.A., Fletcher, A.C., Grasby, P.M. (1997) Absence of radioactive lipophilic metabolites in monkey and human plasma from 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635 - advantages in PET for signal contrast and biomathematical modelling. Nucl. Med. Biol. (submitted).Google Scholar
- 11.Farde, L., Ginovart, N., Halldin, C., Ito, H., Lundkvist, C., Swahn, C.G., McCarron, J.A. and V.W. Pike. (1997) PET-characterization of [carbonyl11C]WAY..100635 binding to 5-HT1A receptors in the monkey and human brain. Psychopharmacology (submitted).Google Scholar
- 12.Ito, H., Nyberg, S., Halldin, C., Lundkvist, C., Farde, L. (1997) Positron emission tomography imaging of 5-HT2A receptors with [11C]MDL 100907. J. Nucl. Med. (submitted).Google Scholar