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

Abstract

Abstract DR4446 (1‐methyl‐2a‐[4‐(4,5,6,7‐tetrahydrothieno[3,2‐ c ]pyridin‐5‐yl)butyl]‐2 a ,3,4,5‐tetrahydro‐1H‐benz[ cd ]indole‐2‐one) is a potent 5‐HT 7 receptor antagonist ( K i =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/μmol 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. Copyright © 2002 John Wiley & Sons, Ltd.