Preclinical and a first-in man studies on [¹¹C]CB184 for imaging 18 kDa translocator protein by positron emission tomography

Objectives The 18 kDa translocator protein (TSPO) overexpression is related to microglial activation and hence considered as an ideal biomarker of neuroinflammation. An imidazopyridineacetamide, N,N-di-n-propyl-2-[2-(4-[¹¹C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([¹¹C]CB184), is a potential radioligand for evaluation of TSPO overexpression in the brain by positron emission tomography (PET). In the present study, we optimized a manufacturing process of [¹¹C]CB184 injection for clinical use and performed preclinical and first-in-man PET studies.

Methods [¹¹C]CB184 was synthesized by O-methylation of the desmethyl precursor with [¹¹C]methyl triflate in the presence of NaOH at room temperature. In vitro selectivity of CB184 was characterized. The radiation absorbed-dose by [¹¹C]CB184 in humans was calculated from mouse distribution data. The acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is more than 10,000−fold the clinical equivalent dose of [¹¹C]CB184, was evaluated. The acute toxicity of [¹¹C]CB184 injection in rats at a dose of 400-fold the postulated administration dose of 740 MBq [¹¹C]CB184 was also evaluated after the decay-out of ¹¹C. The mutagenicity of CB184 was studied by a reverse mutation test in S. typhimurium and E. Coli (Ames test). The pharmacological effect of CB184 injection in mice was studied by an open field test. The first clinical PET imaging of TSPO with [¹¹C]CB184 in two normal volunteer was also performed.

Results A suitable preparation method for [¹¹C]CB184 injection was established. CB184 had low affinity for a 28-standard receptor binding profile. The radiation absorbed-dose by [¹¹C]CB184 in humans was low enough for clinical use, and no acute toxicity of CB184 and [¹¹C]CB184 injection was found. No mutagenic activity was observed for CB184. No apparent effect of CB184 was observed in mice locomotor activity and anxiety status. We safely performed brain imaging by PET with [¹¹C]CB184 in two normal volunteer. A 90-minute dynamic scan showed a rapid initial uptake of the radioactivity in the brain followed by prompt clearance. The highest uptake of [¹¹C]CB184 was found in the thalamus; however, regional differences in brain radioactivity were small. Peripherally, [¹¹C]CB184 was metabolized in human: 30% of the radioactivity in plasma was detected as the unchanged form for 60 min.

Conclusions These results demonstrate that [¹¹C]CB184 is a suitable radioligand to use in clinical trials for imaging TSPO in the human brain, providing acceptable radiation dose and pharmacological safety at the dose required for adequate PET imaging.