Synthesis of two novel [18F]fluorobenzene-containing radiotracers via spirocyclic iodonium ylides and positron emission tomography imaging of translocator protein (18 kDa) in ischemic brain

Abstract

Two novel radiotracers, namely, N-(4-[¹⁸F]fluorobenzyl)-N-methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([¹⁸F]5) and 2-(5-(4-[¹⁸F]fluorophenyl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide ([¹⁸F]6), were developed for positron emission tomography (PET) imaging of translocator protein (18 kDa) (TSPO) in ischemic brain in this study. The two radiotracers with a [¹⁸F]fluorobenzene ring were derived from the corresponding [¹⁸F]fluoroethyl tracers [¹⁸F]7 and [¹⁸F]8 which underwent [¹⁸F]defluoroethylation in vivo easily. [¹⁸F]5 or [¹⁸F]6 was synthesized by the radiofluorination of the spirocyclic iodonium ylide precursor 10 or 17 with [¹⁸F]F⁻ in 23 ± 10% (n = 7) or 56 ± 9% (n = 7) radiochemical yields (decay-corrected, based on [¹⁸F]F⁻). [¹⁸F]5 and [¹⁸F]6 showed high in vitro binding affinities (K_i = 0.70 nM and 5.9 nM) for TSPO and moderate lipophilicities (log D = 2.9 and 3.4). Low uptake of radioactivity for both radiotracers was observed in mouse bones. Metabolite analysis showed that the in vivo stability of [¹⁸F]5 and [¹⁸F]6 was improved in comparison to the parent radiotracers [¹⁸F]7 and [¹⁸F]8. In particular, no radiolabelled metabolite of [¹⁸F]5 was found in the mouse brains at 60 min after the radiotracer injection. PET studies with [¹⁸F]5 on ischemic rat brains revealed a higher binding potential (BP_ND = 3.42) and maximum uptake ratio (4.49) between the ipsilateral and contralateral sides. Thus, [¹⁸F]5 was shown to be a useful PET radiotracer for visualizing TSPO in neuroinflammation models.