TY - JOUR T1 - Evaluation of <sup>11</sup>C-LSN3172176 as a Novel PET Tracer for Imaging M<sub>1</sub> Muscarinic Acetylcholine Receptors in Nonhuman Primates JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1147 LP - 1153 DO - 10.2967/jnumed.118.222034 VL - 60 IS - 8 AU - Nabeel B. Nabulsi AU - Daniel Holden AU - Ming-Qiang Zheng AU - Frederic Bois AU - Shu-Fei Lin AU - Soheila Najafzadeh AU - Hong Gao AU - Jim Ropchan AU - Teresa Lara-Jaime AU - David Labaree AU - Anupama Shirali AU - Lawrence Slieker AU - Cynthia Jesudason AU - Vanessa Barth AU - Antonio Navarro AU - Nancy Kant AU - Richard E. Carson AU - Yiyun Huang Y1 - 2019/08/01 UR - http://jnm.snmjournals.org/content/60/8/1147.abstract N2 - The M1 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 M1-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 11C-LSN3172176 (ethyl 4-(6-(methyl-11C)-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in nonhuman primates. Methods: 11C-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 M1-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. Results: 11C-LSN3172176 was synthesized with greater than 99% radiochemical purity and high molar activity. In rhesus monkeys, 11C-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/cm3) in all known M1 mAChR–rich brain regions. Pretreatment with scopolamine and AZD6088 significantly reduced the brain uptake of 11C-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. Conclusion: 11C-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 M1 AChR. ER -