Synthesis, Radiosynthesis, and Biological Evaluation of Fluorine-18-Labeled 2 beta-Carbo(fluoroalkoxy)-3 beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: Candidate Radioligands for In Vivo Imaging of the Serotonin Transporter with Positron Emission T

摘要

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 cynomolous monkeys with [F-18]1-[F-18]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 [F-18]I, which demonstrated that the uptake of 1 was not influenced by anesthesia. Chase studies with the SERT ligand 15 displaced [F-18]1-[F-18]4, but chase studies with the DAT ligand 16 did not displace [F-18]1-[F-18]4 thus indicating that the tracers were binding specifically to the SERT.