Synthesis and Preclinical Evaluation of the First Carbon-11 Labeled PET Tracers Targeting Substance P(1–7)

[Image: see text] Two potent SP(1–7) peptidomimetics have been successfully radiolabeled via [(11)C]CO(2)-fixation with excellent yields, purity, and molar activity. l-[(11)C]SP(1–7)-peptidomimetic exhibited promising ex vivo biodistribution profile. Metabolite analysis showed that l-[(11)C]SP(1–7)-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-[(11)C]SP(1–7)-peptidomimetic. A slight decrease in SUV value was observed after pretreatment with natural peptide SP(1–7) in spinal cord for l-[(11)C]SP(1–7)-peptidomimetic. On the contrary, blocking using cold analogues of l- and d-[(11)C]tracers did not reduce the tracers’ brain and spinal cord exposure. In summary, PET scanning of l- and d-[(11)C]SP(1–7)-peptidomimetics confirms rapid blood–brain barrier and blood–spinal-cord barrier penetration. Therefore, further validation of these two tracers targeting SP(1–7) is needed in order to define a new PET imaging target and select its most appropriate radiopharmaceutical.