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

• Published in: Journal of medicinal chemistry 2008-12, Vol.51 (24), p.7788-7799
• Main Authors: Stehouwer, Jeffrey S, Jarkas, Nachwa, Zeng, Fanxing, Voll, Ronald J, Williams, Larry, Camp, Vernon M, Malveaux, Eugene J, Votaw, John R, Howell, Leonard, Owens, Michael J, Goodman, Mark M
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800781a

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.