Synthesis, Radiosynthesis, and Biological Evaluation of Fluorine-18-Labeled 2β-Carbo(fluoroalkoxy)-3β-(3′-((Z)-2-haloethenyl)phenyl)nortropanes: Candidate Radioligands for In Vivo Imaging of the Serotonin Transporter with Positron Emission Tomography

Abstract

The meta-vinylhalide fluoroalkyl ester nortropanes 1−4 were synthesized as ligands of the serotonin transporter (SERT) for use as positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that 1−4 have a high affinity for the SERT (K_i values = 0.3−0.4 nM) and are selective for the SERT over the dopamine and norepinephrine transporters (DAT and NET). MicroPET imaging in anesthetized cynomolgus monkeys with [¹⁸F]1−[¹⁸F]4 demonstrated that all four tracers behave similarly with peak uptake in the SERT-rich brain regions achieved after 45−55 min, followed by a steady washout. An awake monkey study was performed with [¹⁸F]1, which demonstrated that the uptake of [¹⁸F]1 was not influenced by anesthesia. Chase studies with the SERT ligand 15 displaced [¹⁸F]1−[¹⁸F]4, but chase studies with the DAT ligand 16 did not displace [¹⁸F]1−[¹⁸F]4 thus indicating that the tracers were binding specifically to the SERT.