Synthesis and preliminary PET study of the 5‐HT₇ receptor antagonist [¹¹C]DR4446

Abstract

Summary 5,6,pyridin-5-yl)butyl]-2a,3,4,5-tetrahydro-1H-benz[cd ]indole-2-one) is a potent 5-HT 7 receptor antagonist (K i ¼ 9:7 nM) with a high selectivity over other 5-HT family receptors (K i for 5-HT 1A : 770 nM; for other 5-HT receptors: >1000 nM). As a positron emission tomography (PET) tracer for the 5-HT 7 receptor, [ 11 C]DR4446 was synthesized at high radiochemical purity (>98%) with specific activity of 73-120 GBq/mmol at the end of synthesis by the alkylation of the desmethyl precursor (1) with [ 11 C]CH 3 I in the presence of NaH. A PET study in monkey demonstrated that [ 11 C]DR4446 had good permeability into the brain, and had a specific binding component in the brain regions including the thalamus, possibly an area in the 5-HT 7 receptors. Metabolite analysis showed that [ 11 C]DR4446 was relatively stable and low percentages of two radio-labeled metabolites were detected in the plasma of monkey using HPLC.

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

“…7,8 Most recently, 18 F-labeled SB-269970 derivatives were synthesized and evaluated in vivo in cats, 9,10 but in the absence of a validated reference region or an arterial input function it was not possible to fully evaluate the validity of those radiolabeled compounds. 11…”

“…T he relatively recently discovered G-protein coupled 5-HT 7 receptor has been implicated in various central nervous system (CNS) disorders such as schizophrenia, depression, epilepsy, migraine, and in the control of circadian rhythm. 1 For example, the atypical antipsychotic drug amisulpride has antidepressant effects, 2,3 and a study in 5-HT 7 receptor knockout mice supports that the 5-HT 7 receptor antagonism of amisulpride alleviates depression symptoms.…”

“…1 For example, the atypical antipsychotic drug amisulpride has antidepressant effects, 2,3 and a study in 5-HT 7 receptor knockout mice supports that the 5-HT 7 receptor antagonism of amisulpride alleviates depression symptoms. 4 Other atypical antipsychotics also have relatively high affinity for the 5-HT 7 receptor, but their involvement in alleviating depressive symptoms through blocking the 5-HT 7 receptor remains to be investigated. 5,6 In vivo studies of cerebral 5-HT 7 receptor binding in humans would thus provide a significant advance in the understanding of the above-mentioned physiology and pathophysiology.…”

“…4 Other atypical antipsychotics also have relatively high affinity for the 5-HT 7 receptor, but their involvement in alleviating depressive symptoms through blocking the 5-HT 7 receptor remains to be investigated. 5,6 In vivo studies of cerebral 5-HT 7 receptor binding in humans would thus provide a significant advance in the understanding of the above-mentioned physiology and pathophysiology. Positron emission tomography (PET) is used to quantify neuroreceptor binding in vivo, and the availability of an appropriate PET radiotracer for the 5-HT 7 receptor would be of particular interest.…”

“…7,8 Most recently, 18 F-labeled SB-269970 derivatives were synthesized and evaluated in vivo in cats, 9,10 but in the absence of a validated reference region or an arterial input function it was not possible to fully evaluate the validity of those radiolabeled compounds. 11 Several lead structures of 5-HT 7 receptor ligands have been identified within various structural classes. 12 Among these structures, phenylpiperazinyl-butyloxindoles display an interesting selectivity profile (Figure 1).…”