Development of ¹⁸F-labeled 2-phenylimidazo[1,2-a]pyridine analog, ¹⁸F-CB251, for TSPO-selective PET radiotracer

Objectives We report herein the synthesis, the characterization, and in vivo evaluation of a new TSPO PET imaging agent, ¹⁸F-CB251 ([¹⁸F]1, 2-(6,8-dichloro-2-(4-[¹⁸F]fluoroethoxyphenyl)imidazole[1,2-a]pyridine-3-yl)-N,N-dipropylacetamide), in a rat model of neuroinflammation.

Methods [¹⁸F]1 was prepared by incorporating of fluorine-18 into the tosylate precursor in a single-step radiolabeling procedure. The affinity toward TSPO of 1 was measured on membrane extracts of C6 glioma cells. Tissue distribution was performed in normal ICR mice. Comparison of neuroinflammation imaging with [¹⁸F]1 versus [¹¹C]PBR28 was performed in the same lipopolysaccharide (LPS)-induced neuroinflammatory rat model.

Results [¹⁸F]1 has been efficiently synthesized in 8.2±2.5% of radiochemical yield (n.d.c.) with >99% of radiochemical purity, 129±25 GBq/μmol of specific activity. The binding affinity (IC₅₀=0.27 nM) of the 1 was shown in the subnanomolar value. [¹⁸F]1 was highly accumulated in the TSPO-enriched tissues i.e., lung, heart and kidney, whereas it exhibited comparatively low uptake in liver and brain. In PET imaging studies in neuroinflammatory rat model, [¹⁸F]1 was selectively accumulated in the ipsilateral striatum and rapidly approached the highest target-to-background ratio (2.7 times) at early imaging time. The ratio of AUC in the ipsilateral and contralateral striatum of [¹⁸F]1 was comparable to that of [¹¹C]PBR28. In blocking experiment using flumazenil and PBR28, flumazenil did not intercept the uptake of [¹⁸F]1 in the ipsilateral area, whereas significantly decreased after injection with PBR28.

Conclusions Taken together, [¹⁸F]1 hold promise as a neuroinflammation PET imaging agent in the field of brain degenerative disease.