Abstract
Objective
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.
Methods
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.
Results
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.
Conclusions
[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.
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Acknowledgments
We thank Mr. Kunpei Hayashi, Mr. Masanari Sakai, and Ms. Hatsumi Endo for technical assistance. This work was supported in part by the Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology, Japan (21-5), KAKENHI (24730642, 15H03103, 26115532, 25560382, 25293271). All authors disclose no potential conflicts of interest.
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Toyohara, J., Sakata, M., Hatano, K. et al. Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography. Ann Nucl Med 30, 534–543 (2016). https://doi.org/10.1007/s12149-016-1094-7
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DOI: https://doi.org/10.1007/s12149-016-1094-7