Preliminary biological evaluations of first brain‐penetrant GPR119‐based radiotracer in rodents and non‐human primates

Background G-protein-coupled receptors (GPCRs) plays a key role in regulating glucose metabolism. While GPR119 (an important GPCR) agonists have shown potential for improving neurologic and cognitive function patients with AD type2 diabetes mellitus (T2DM), clinical interventions targeting will require accurate vivo measures such as PET imaging. We recently synthesized series of novel piperdine analogs, identifying two analogs (T1 T2) high binding potency (2-5 nM) radiochemistry. Here we report their radiochemistry initial biological evaluations neuronal cells, normal rodents, monkeys (vervets). Method [18F]T1/T2 was performed TRASIS-AIO automated module following [18F]¯-based nucleophilic substitution corresponding precursors. [18F]T1 T2 vitro assays were three patient-derived cell lines different expression (MDM-MD-23198%) specific activities (∼3800-4500 mCi/µmol), decay corrected to end synthesis. Radioactive lower MDM-MD-231 cells (lowest expression) higher HepG2 (higher expression); also significantly increased T1/T2 treatments compared baseline. [18F]T2 showed slightly better (SUVmax 0.35±0.07 Vs. 0.55±0.09 g/mL). Biodistribution (%ID/mg 1.01±0.09) uptake. SUVmax (avg 2.6±0.1 g/mL) TACs both monkey brains demonstrated rapid distribution across BBB within 10 favorable clearance 90 tracer injection (Fig 1). Conclusion Radiochemistry successfully optimized. Cell direct relationships between radiotracer expression. MicroPET imaging, rodents excellent pharmacokinetics, indicating penetration. These data suggest the first time that humans or T2DM.