Radiosynthesis of 6-[18F]fluoro-PBR28, a candidate for imaging brain peripheral benzodiazepine receptors with PET

Objectives [¹¹C]PBR28 is a recently reported compound displaying exceptional properties for the in vivo imaging of the peripheral benzodiazepine receptor (or TSPO 18 kDa) using PET (Briard et al., J Med Chem. 2008, 51:17-30 ; Fujita et al., Neuroimage2008, 39:1289-98 and Imaizumi et al., Neuroimage2008, 40:43-52). This meta/para-bi-substituted pyridine leaves open the option of fluorine introduction at an ortho position, and therefore offers an opportunity for labeling with the longer half-life positron-emitter fluorine-18, which is the subject of the work presented herein.

Methods 6-Fluoro-PBR28 (N-(2-methoxybenzyl)-N-(6-fluoro-4-phenoxypyridinyl-3-yl)acetamide) and its 6-bromo analog were synthesized from commercially available 4-chloro-3-nitropyridine. Fluorine-18 labeling involves: (A) reaction of K[¹⁸F]F-Kryptofix^®222 with 2-3 mg of the bromo derivative at 165°C for 5 min in DMSO, (B) C-8 PrepSep cartridge pre-purification, (C) semi-preparative HPLC purification and (D) SepPak^®Plus-based formulation.

Results 6-Fluoro-PBR28 and its bromo analog were both synthesized in six chemical steps, respectively in 16% and 19% overall yield. Ready-to-inject 6-[¹⁸F]fluoro-PBR28 (>95% radiochemically pure) was prepared using our Zymate-XP robotic system, in 90 minutes and 10% non-decay-corrected yield. SRA ranged from 74 to 111 GBq/micromole.

Conclusions 6-Fluoro-PBR28 was labeled with fluorine-18 in one single step using a bromine-for-fluorine heteroaromatic substitution. Dynamic µPET studies are currently underway in our rodent model of neuroinflammation (unilaterally AMPA-induced striatum-lesioned rats).