Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT; and
Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT; and.
J Nucl Med. 2019 Aug;60(8):1147-1153. doi: 10.2967/jnumed.118.222034. Epub 2019 Feb 7.
The M muscarinic acetylcholine receptor (mAChR) plays an important role in learning and memory, and therefore is a target for development of drugs for treatment of cognitive impairments in Alzheimer disease and schizophrenia. The availability of M-selective radiotracers for PET will help in developing therapeutic agents by providing an imaging tool for assessment of drug dose-receptor occupancy relationship. Here we report the synthesis and evaluation of C-LSN3172176 (ethyl 4-(6-(methyl-)-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in nonhuman primates. C-LSN3172176 was radiolabeled via the Suzuki-Miyaura cross-coupling method. PET scans in rhesus macaques were acquired for 2 h with arterial blood sampling and metabolite analysis to measure the input function. Blocking scans with scopolamine (50 μg/kg) and the M-selective agent AZD6088 (0.67 and 2 mg/kg) were obtained to assess tracer binding specificity and selectivity. Regional brain time-activity curves were analyzed with the 1-tissue-compartment model and the multilinear analysis method (MA1) to calculate regional distribution volume. Nondisplaceable binding potential values were calculated using the cerebellum as a reference region. C-LSN3172176 was synthesized with greater than 99% radiochemical purity and high molar activity. In rhesus monkeys, C-LSN3172176 metabolized rapidly (29% ± 6% parent remaining at 15 min) and displayed fast kinetics and extremely high uptake in the brain. Imaging data were modeled well with the 1-tissue-compartment model and MA1 methods. MA1-derived distribution volume values were high (range, 10-81 mL/cm) in all known M mAChR-rich brain regions. Pretreatment with scopolamine and AZD6088 significantly reduced the brain uptake of C-LSN3172176, thus demonstrating its binding specificity and selectivity in vivo. The cerebellum appeared to be a suitable reference region for derivation of nondisplaceable binding potential, which ranged from 2.42 in the globus pallidus to 8.48 in the nucleus accumbens. C-LSN3172176 exhibits excellent in vivo binding and imaging characteristics in nonhuman primates and appears to be the first appropriate radiotracer for PET imaging of human M AChR.
M 毒蕈碱乙酰胆碱受体（mAChR）在学习和记忆中发挥着重要作用，因此成为开发治疗阿尔茨海默病和精神分裂症认知障碍药物的靶点。用于正电子发射断层扫描（PET）的 M 选择性放射性示踪剂的可用性将通过提供评估药物剂量-受体占有率关系的成像工具来帮助开发治疗剂。在这里，我们报告了 C-LSN3172176（乙基 4-（6-（甲基）-2-氧代吲哚啉-1-基）-[1,4'-联哌啶]-1'-羧酸酯）在非人灵长类动物中的合成和评估。C-LSN3172176 通过 Suzuki-Miyaura 交叉偶联法进行放射性标记。在恒河猴中进行了 2 小时的 PET 扫描，同时进行动脉采血和代谢产物分析，以测量输入函数。使用东莨菪碱（50 μg/kg）和 M 选择性药物 AZD6088（0.67 和 2 mg/kg）进行阻断扫描，以评估示踪剂结合的特异性和选择性。使用单组织室模型和多线性分析方法（MA1）分析脑区时间-活性曲线，以计算脑区分布容积。使用小脑作为参照区计算不可置换结合潜能值。C-LSN3172176 的放射化学纯度大于 99%，比活度高。在恒河猴中，C-LSN3172176 代谢迅速（15 分钟时仍有 29%±6%的母体），在大脑中具有快速的动力学和极高的摄取率。成像数据与单组织室模型和 MA1 方法拟合良好。MA1 衍生的分布容积值在所有已知富含 M mAChR 的脑区均较高（范围为 10-81 mL/cm）。用东莨菪碱和 AZD6088 预处理可显著降低 C-LSN3172176 在大脑中的摄取，从而证明其在体内的结合特异性和选择性。小脑似乎是推导不可置换结合潜能的合适参照区，其范围从苍白球的 2.42 到伏隔核的 8.48。C-LSN3172176 在非人类灵长类动物中表现出优异的体内结合和成像特性，似乎是用于人类 M AChR PET 成像的首个合适的放射性示踪剂。
