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. [1]. 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) [4]. 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 [5]. WAY-100635 has recently been labelled with 11C also in the carbonyl position and examined in the human brain with PET [6].