Synthesis and evaluation of a novel TSPO radiotracer [¹⁸F]FM-PBR28 in a rat model of neuroinflammation: A PET study in comparison with [¹¹C]PBR28

Objectives The translocator protein (TSPO, 18 kDa) is implicated in neuroinflammation including several neurodegenerative disorders. To develop a PET radiotracer for imaging the TSPO, [¹⁸F]fluoromethyl group introduced PBR28 derivative was synthesized and evaluated in neuroinflammation rat models and also compared with [¹¹C]PBR28.

Methods The novel radiotracer, [¹⁸F]FM-PBR28 (N-(2-[¹⁸F]fluoromethoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide) was prepared from nucleophilic aliphatic substitution on triazolium triflate-PBR28 precursor with fluorine-18 in a single-step radiolabeling procedure. [¹¹C]PBR28 was produced in FXC-pro module using [¹¹C]MeOTf from phenolic PBR28 precursor. Comparison of neuroinflammation imaging with [¹⁸F]FM-PBR28 versus [¹¹C]PBR28 was performed in rat models, including IC₅₀, logP, and metabolic stability.

Results [¹⁸F]FM-PBR28 has been efficiently synthesized in 25.8±3.2% of radiochemical yield (d.c., n=11). [¹⁸F]FM-PBR28 and PBR28 showed similar in vitro binding affinity and log P values. In a unilateral excitotoxic striatal lesion in the rat, [¹⁸F]FM-PBR28 was selectively accumulated in the lesioned striatum about 3.7 times greater than in its contralateral homologue at 35 min postinjection. However, this specific uptake of [¹¹C]PBR28 in the lesioned striatum was about 2.8 times versus non lesioned striatum, whereas it required up to 100 min postinjection to achieve a similar effect. In blocking studies, [¹⁸F]FM-PBR28 exhibited the high specific and selective binding for TSPO in the traumatic brain injury. [¹⁸F]FM-PBR28 was shown to be stable (>98%, 4 h) in human serum in vitro as well as in rat brain (>96%, 1 h) in vivo.

Conclusions An advanced method for introducing F-18 into fluoromethoxy analog proceeds efficiently and rapidly under conditions suitable for [¹⁸F]FM-PBR28. Our results suggest that [¹⁸F]FM-PBR28 hold promise as a novel TSPO radiotracer in the field of brain disorders.