Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations

Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (K_i = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct S_NAr radiofluorination, ¹⁸F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D_7.4 measurement indicated ¹⁸F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with ¹⁸F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. ¹⁸F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of ¹⁸F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.