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SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide) is the lead compound of an original pyridazinoindole series of potent and highly selective TSPO (peripheral benzodiazepine receptor) ligands. Isotopic labeling of SSR180575 with the short-lived positron-emitter carbon-11 (T1/2: 20.38 min) at its 5-methylpyridazino[4,5-b]indole moiety as well as at its N,N-dimethylacetamide function by methylation of the corresponding nor-analogues was investigated. Best results in terms of radiochemical yields and purities were obtained for the preparation of [indole-N-methyl-11C]SSR180575, where routine production batches of 4.5–5.0 GBq of radiochemically pure (>99%) i.v. injectable solutions (specific radioactivities: 50–90 GBq/µmol) could be prepared within a total synthesis time of 25 min (HPLC purification included) starting from a 55 GBq [11C]CO2 cyclotron production batch (non-decay-corrected overall radiochemical yields: 8–9%). The process comprises (1) trapping at −10°C of [11C]methyl triflate in DMF (300 µl) containing 0.2–0.3 mg of the indole precursor for labeling and 4 mg of K2CO3 (excess); (2) heating at 120°C for 3 min; (3) dilution of the residue with 0.5 ml of the HPLC mobile phase and (4) purification using semi-preparative reversed-phase HPLC (Zorbax® SB-C-18). In vivo pharmacological properties of [indole-N-methyl-11C]SSR180575 as a candidate for imaging neuroinflammation with positron emission tomography are currently evaluated. Copyright © 2010 John Wiley & Sons, Ltd.

Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects.Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats.The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO.[(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.