RT Journal Article SR Electronic T1 Evaluation of 11C-LSN3172176 as a Novel PET Tracer for Imaging M1 Muscarinic Acetylcholine Receptors in Nonhuman Primates JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1147 OP 1153 DO 10.2967/jnumed.118.222034 VO 60 IS 8 A1 Nabeel B. Nabulsi A1 Daniel Holden A1 Ming-Qiang Zheng A1 Frederic Bois A1 Shu-Fei Lin A1 Soheila Najafzadeh A1 Hong Gao A1 Jim Ropchan A1 Teresa Lara-Jaime A1 David Labaree A1 Anupama Shirali A1 Lawrence Slieker A1 Cynthia Jesudason A1 Vanessa Barth A1 Antonio Navarro A1 Nancy Kant A1 Richard E. Carson A1 Yiyun Huang YR 2019 UL http://jnm.snmjournals.org/content/60/8/1147.abstract AB 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.