Development of serotonin transporter brain imaging agents for use in positron emission tomography and single photon emission computed tomography

Radioimaging of brain serotonin transporters (SERT) has potential applications in the study of normal functions and disease states involving the serotonergic system and importantly, it can be performed in living animals and humans. It was hypothesized that a successful 18F labeled SERT selective tracer for positron emission tomography could be developed by the addition of a fluoroalkoxy substituent on a diaryl sufide core. A novel series of such ligands were synthesized and evaluated It was found that the fluoroalkoxy substituent did allow for good radiochemical yields, and two of the compounds (hydrogen at the 4'-position and fluoroethoxy or fluoropropoxy substituent at the 5-position) showed excellent target to non-target ratios through biodistribution studies. Autoradiography and PET imaging with the fluoropropoxy derivative showed tracer localization to SERT-rich regions in the brain, and SERT selectivity was demonstrated through blocking or chase studies using monoamine transporter inhibitors.From the promising results of the fluoroethoxy and fluoropropoxy compounds, it was of interest to examine how increasing the fluoroalkoxy chain length would affect radiotracer properties such as binding affinity, selectivity, brain uptake, and target to non-target ratios. Fluorobutoxy and fluoropentoxy derivatives were synthesized, and the structure activity relationships of the four compounds were compared. It was determined that increasing the carbon chain length to four or five carbons decreased the target to non-target ratio The fluoroethoxy and fluoropropoxy derivatives appeared to be the superior candidates, and though both were promising, the fluoropropoxy derivative, consequently named 18F-FPBM, was chosen for further validation studies. In preliminary studies 18F-FPBM was successful in detecting varying degrees of SERT binding loss through PET imaging in a Parkinson's disease rat model. Results from in vitro autoradiography followed the same trend seen through PET imaging, and parallel studies with the VMAT2 ligand, 18F-AV133, and DAT ligand, 125I-IPT, supported results from the 18F-FPBM studies.A potential new SERT tracer, 125I-FlipADAM, for single photon emission computed tomography (SPECT) was also synthesized and evaluated. 125I-F1ipADAM showed faster clearance from the brain and time to binding equilibrium when compared to 125I-ADAM, a higher target to non-target ratio when compared to 125I-IDAM, and may be an improved SERT-selective tracer for SPECT.