Synthesis and Evaluation of [11C]SB207145 as the First In Vivo Serotonin 5-HT4 Receptor Radioligand for PET Imaging in Man

The aim of this work was to develop a PET radiotracer which would enable the study of central serotonin 5-HT4 receptors in man using positron emission tomography (PET). A procedure was developed for labelling SB207145, a potent and selective 5-HT4 antagonist, with the short-lived positron emitting radionuclide 11C. Alkylation of the corresponding desmethyl compound with 11C-methyl iodide afforded [11C]SB207145 in 50 - 60 %radiochemical yield (decay corrected to end of cyclotron bombardment), specific activities of > 50 GBq/μmole and radiochemical purities greater than 95%. PET studies in pig showed [11C]SB207145 rapidly entered the brain reaching peak concentrations at 10 - 20 mins post administration, followed by washout from tissue. In humans the tissue kinetics of the tracer was slower, reaching peak tissue concentrations at 30 - 60 mins post administration. In both species, the observed rank order of regional brain concentrations was striatum > thalamus > cortical regions > cerebellum, consistent with the known distribution and concentration of 5-HT4 receptors from in vitro studies. In pig, on administration of 0.5 mg/kg SB207040, a selective 5-HT4 antagonist, the specific binding of [11C]SB207145 was reduced to level of the cortex, demonstrating saturability of the 5-HT4 receptor population. In conclusion, a new PET radioligand is described which enables the study of 5-HT4 receptors in vivo in humans for the first time using PET.