Toyohara Jun, Sakata Muneyuki, Wu Jin, Ishikawa Masatomo, Oda Keiichi, Ishii Kenji, Iyo Masaomi, Hashimoto Kenji, Ishiwata Kiichi
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan.
Ann Nucl Med. 2009 May;23(3):301-9. doi: 10.1007/s12149-009-0240-x. Epub 2009 Apr 1.
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.
[(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.
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.
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.
4-[(11)C]甲基苯基2,5-二氮杂双环[3.2.2]壬烷-2-羧酸酯（[(11)C]CHIBA-1001）是选择性α7烟碱型乙酰胆碱受体（α7 nAChR）部分激动剂4-溴苯基1,4-二氮杂双环[3.2.2]壬烷-4-羧酸酯（SSR180711）的4-甲基取代衍生物，是一种通过正电子发射断层扫描（PET）在脑中绘制α7 nAChR图谱的潜在放射性配体。在本研究中，我们使用[(11)C]CHIBA-1001进行了临床前和首次临床PET研究，以对人脑中的α7 nAChR进行成像。
[(11)C]CHIBA-1001通过在钯促进的Stille交叉偶联反应中用[(11)C]CH3I对三丁基锡前体进行甲基化来合成。根据小鼠体内分布数据计算[(11)C]CHIBA-1001在人体中的辐射吸收剂量。评估了剂量为3.20 mg/kg体重的CHIBA-1001的急性毒性，该剂量是[(11)C]CHIBA-1001临床等效剂量的41000多倍。通过鼠伤寒沙门氏菌回复突变试验（Ames试验）研究CHIBA-1001的致突变性。通过高效液相色谱法对小鼠脑内代谢物进行分析。还在一名正常志愿者中进行了用[(11)C]CHIBA-1001对α7 nAChR的首次临床PET成像。
建立了适合[(11)C]CHIBA-1001注射的制备方法。[(11)C]CHIBA-1001在人体中的辐射吸收剂量低至足以用于临床，且未发现CHIBA-1001有急性毒性或致突变性。尽管外周[(11)C]CHIBA-1001会降解，但在小鼠脑中大部分放射性被检测为未变化的形式。我们成功地在一名正常志愿者中用[(11)C]CHIBA-1001通过PET进行了脑成像。一次90分钟的动态扫描显示放射性在脑中快速积累并逐渐清除。[(11)C]CHIBA-1001的最高分布容积出现在丘脑；然而，脑内放射性的区域差异较小。在人体外周，[(11)C]CHIBA-1001是稳定的：血浆中>80%的放射性在60分钟内被检测为未变化的形式。
这些结果表明[(11)C]CHIBA-1001是一种适用于在临床试验中对人脑中α7 nAChR进行成像的放射性配体，在进行充分PET成像所需的剂量下提供了可接受的剂量学和药理安全性。
