[Acetamide-¹⁸F]Fluoro-SSR180575: A potent radiofluorinated analog of the TSPO ligand SSR180575

Objectives SSR180575 is the lead compound of a recently developed and promising series of ligands targeting the translocator protein 18 kDa (TSPO). Addition of a single radiofluorine atom at the acetamide position led to [acetamide-¹⁸F]fluoro-SSR180575 (2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)-2-[¹⁸F]fluoro-N,N-dimethylacetamide), a novel highly potent structure, which synthesis, preliminary in vitro data and in vivo PET imaging are presented herein.

Methods Fluoro-SSR180575 and its tosylated analog as precursor for fluorine-18-labeling were synthesized from SSR180575 in 2 steps. In vitro binding affinity for the TSPO was determined by competition with [³H]PK11195. [¹⁸F]Fluoro-SSR180575 was prepared using a TRACERLab FX-N Pro synthesizer (GEMS) using standard conditions (K[¹⁸F]F-Kryptofix^®222, DMSO, 120°C, 5 min then SepPak^® Alumina N™ and HPLC purification followed by SepPak^® cartridge-based formulation). PET-imaging (Inveon PET Siemens) was performed on our in-house-developed rat model of acute local neuroinflammation (Wistar rat, excitotoxic AMPA-mediated brain lesion in the right striatum) and results were compared to [¹¹C]SSR180575 and [¹¹C]PK11195.

Results Fluoro-SSR180575 and its tosylated analog were obtained in 29% and 10% yields, respectively. Fluoro-SSR180575 exhibited a high affinity for the TSPO (Ki = 1.6 nM). [¹⁸F]fluoro-SSR180575 (> 99% radiochemically pure) was obtained in 55-60 min and 7-10% ndc yields, with SRA ranging from 40 to 80 GBq/µmol. In PET experiments, [¹⁸F]Fluoro-SSR180575 showed a high contrast between the lesioned area and the corresponding area in the intact contralateral hemisphere: ipsi-to-contra ratio: 3.08 ± 0.41 at 60 min post-injection, a value also higher than those reported for [¹¹C]PK11195 and [¹¹C]SSR180575 in the same animal model (1.65 ± 0.20 and 2.70 ± 0.13, respectively).

Conclusions [acetamide-¹⁸F]fluoro-SSR180575 was successfully prepared and µPET studies in rats demonstrate the potential of this novel radiotracer to image neuroinflammation.

Research Support Supported in part by the FP7 INMiND program.