Synthesis and Preclinical Evaluation of the First Carbon-11 Labeled PET Tracers Targeting Substance P1-7

Two potent SP1-7 peptidomimetics have been successfully radiolabeled via [C-11]CO2-fixation with excellent yields, purity, and molar activity. L-[C-11]SP1-7-peptidomimetic exhibited promising ex vivo biodistribution profile. Metabolite analysis showed that L-[C-11]SP1-7-peptidomimetic is stable in brain and spinal cord, whereas rapid metabolic degradation occurs in rat plasma. Metabolic stability can be significantly improved by substituting L-Phe for D-Phe, preserving 70% more of intact tracer and resulting in better brain and spinal cord tracer retention. Positron emission tomography (PET) scanning confirmed moderate brain (1.5 SUV; peak at 3 min) and spinal cord (1.0 SUV; peak at 10 min) uptake for L- and D-[C-11]SP1-7-peptidomimetic. A slight decrease in SUV value was observed after pretreatment with natural peptide SP1-7 in spinal cord for L-[C-11]SP1-7-peptidomimetic. On the contrary, blocking using cold analogues of L- and D-[C-11]tracers did not reduce the tracers' brain and spinal cord exposure. In summary, PET scanning of L- and D-[C-11]SP1-7-peptidomimetics confirms rapid blood-brain barrier and blood-spinal-cord barrier penetration. Therefore, further validation of these two tracers targeting SP1-7 is needed in order to define a new PET imaging target and select its most appropriate radiopharmaceutical.