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Annals of Nuclear Medicine
Published in: Annals of Nuclear Medicine 8/2016

01-10-2016 | Original Article

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

Authors: Jun Toyohara, Muneyuki Sakata, Kentaro Hatano, Shuichi Yanai, Shogo Endo, Kenji Ishibashi, Kei Wagatsuma, Kenji Ishii, Kiichi Ishiwata

Published in: Annals of Nuclear Medicine | Issue 8/2016

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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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Metadata
Title
Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography
Authors
Jun Toyohara
Muneyuki Sakata
Kentaro Hatano
Shuichi Yanai
Shogo Endo
Kenji Ishibashi
Kei Wagatsuma
Kenji Ishii
Kiichi Ishiwata
Publication date
01-10-2016
Publisher
Springer Japan
Published in
Annals of Nuclear Medicine / Issue 8/2016
Print ISSN: 0914-7187
Electronic ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-016-1094-7

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