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

We performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[¹¹C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([¹¹C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions.

In vitro selectivity of CB184 was characterized. The radiation absorbed dose by [¹¹C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is >10,000-fold higher than the clinical equivalent dose of [¹¹C]CB184, was evaluated. Acute toxicity of [¹¹C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [¹¹C]CB184 was also evaluated after the decay-out of ¹¹C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [¹¹C]CB184 in a normal human volunteer was performed.

A suitable preparation method for [¹¹C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [¹¹C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [¹¹C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [¹¹C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [¹¹C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [¹¹C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [¹¹C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [¹¹C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.

[¹¹C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.