Synthesis and in Vivo Evaluation of Fluorine-18 and Iodine-123 Labeled 2β-Carbo(2-fluoroethoxy)-3β-(4‘-((Z)-2-iodoethenyl)phenyl)nortropane as a Candidate Serotonin Transporter Imaging Agent

Abstract

2Beta-carbo(2-fluoroethoxy)-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (betaFEpZIENT, 1) was synthesized as a serotonin transporter (SERT) imaging agent for both positron emission tomography (PET) and single photon emission computerized tomography (SPECT). The binding affinity of 1 to human monoamine transporters showed a high affinity for the SERT (Ki = 0.08 nM) with respect to the dopamine transporter (DAT) (Ki = 13 nM) and the norepinephrine transporter (NET) (Ki = 28 nM). In vivo biodistribution and blocking studies performed in male rats demonstrated that [123I]1 was selective and specific for SERT. In vivo microPET brain imaging studies in an anesthetized monkey with [18F]1 showed high uptake in the diencephalon and brainstem with peak uptake achieved at 120 min. A chase study with (R,S)-citalopram.HBr displaced [18F]1 radioactivity from all SERT-rich brain regions. A chase study with the DAT ligand 2beta-carbophenoxy-3beta-(4-chlorophenyl)tropane (9, RTI-113) failed to displace [18F]1, indicating that [18F]1 is specific to the SERT. The in vivo evaluation of [18F]1 indicates that this radiotracer is a good candidate for mapping and quantifying CNS SERT.