Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping alpha7 nicotinic receptors by positron emission tomography.
OBJECTIVE
4-[(11)C]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([(11)C]CHIBA-1001), a 4-methyl-substituted derivative of the selective alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) partial agonist 4-bromophenyl 1,4 diazabicyclo[3.2.2]nonane-4-carboxylate (SSR180711), is a potential radioligand for mapping alpha7 nAChRs in the brain by positron emission tomography (PET). In this study, we performed preclinical and first clinical PET studies using [(11)C]CHIBA-1001 for imaging alpha7 nAChRs in the human brain.


METHODS
[(11)C]CHIBA-1001 was synthesized by methylation of the tributylstannyl precursor with [(11)C]CH(3)I in a palladium-promoted Stille cross-coupling reaction. The radiation absorbed-dose of [(11)C]CHIBA-1001 in humans was calculated from distribution data in mice. The acute toxicity of CHIBA-1001 at a dose of 3.20 mg/kg body weight, which is more than 41,000-fold the clinical equivalent dose of [(11)C]CHIBA-1001, was evaluated. The mutagenicity of CHIBA-1001 was studied by a reverse mutation test in Salmonella typhimurium (Ames test). Metabolite analysis in the mouse brain was carried out by high-performance liquid chromatography. The first clinical PET imaging of alpha7 nAChRs with [(11)C]CHIBA-1001 in a normal volunteer was also performed.


RESULTS
A suitable preparation method for [(11)C]CHIBA-1001 injection was established. The radiation absorbed-dose by [(11)C]CHIBA-1001 in humans was low enough for clinical use, and no acute toxicity or mutagenicity of CHIBA-1001 was found. Most radioactivity in the mouse brain was detected as an unchanged form, although peripherally [(11)C]CHIBA-1001 was degraded. We successfully performed brain imaging by PET with [(11)C]CHIBA-1001 in a normal volunteer. A 90-min dynamic scan showed a rapid accumulation and gradual washout of radioactivity in the brain. The highest distribution volume of [(11)C]CHIBA-1001 was found in the thalamus; however, regional differences in brain radioactivity were small. Peripherally, [(11)C]CHIBA-1001 was stable in humans: >80% of the radioactivity in plasma was detected as the unchanged form for 60 min.


CONCLUSIONS
These results demonstrate that [(11)C]CHIBA-1001 is a suitable radioligand to use in clinical trials for imaging alpha7 nAChRs in the human brain, providing acceptable dosimetry and pharmacological safety at the dose required for adequate PET imaging.
Toyohara
Jun
J
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan.
Sakata
Muneyuki
M
Wu
Jin
J
Ishikawa
Masatomo
M
Oda
Keiichi
K
Ishii
Kenji
K
Iyo
Masaomi
M
Hashimoto
Kenji
K
Ishiwata
Kiichi
K