RT Journal Article SR Electronic T1 Synthesis and Preclinical Evaluation of 11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 777 OP 784 DO 10.2967/jnumed.115.168179 VO 57 IS 5 A1 Nabeel B. Nabulsi A1 Joël Mercier A1 Daniel Holden A1 Stephane Carré A1 Soheila Najafzadeh A1 Marie-Christine Vandergeten A1 Shu-fei Lin A1 Anand Deo A1 Nathalie Price A1 Martyn Wood A1 Teresa Lara-Jaime A1 Florian Montel A1 Marc Laruelle A1 Richard E. Carson A1 Jonas Hannestad A1 Yiyun Huang YR 2016 UL http://jnm.snmjournals.org/content/57/5/777.abstract AB The synaptic vesicle glycoprotein 2A (SV2A) is found in secretory vesicles in neurons and endocrine cells. PET with a selective SV2A radiotracer will allow characterization of drugs that modulate SV2A (e.g., antiepileptic drugs) and potentially could be a biomarker of synaptic density (e.g., in neurodegenerative disorders). Here we describe the synthesis and characterization of the SV2A PET radiotracer 11C-UCB-J ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) in nonhuman primates, including whole-body biodistribution. Methods: 11C-UCB-J was prepared by C-11C-methylation of the 3-pyridyl trifluoroborate precursor with 11C-methyl iodide via the Suzuki–Miyaura cross-coupling method. Rhesus macaques underwent multiple scans including coinjection with unlabeled UCB-J (17, 50, and 150 μg/kg) or preblocking with the antiepileptic drug levetiracetam at 10 and 30 mg/kg. Scans were acquired for 2 h with arterial sampling and metabolite analysis to measure the input function. Regional volume of distribution (VT) was estimated using the 1-tissue-compartment model. Target occupancy was assessed using the occupancy plot; the dissociation constant (Kd) was determined by fitting self-blocking occupancies to a 1-site model, and the maximum number of receptor binding sites (Bmax) values were derived from baseline VT and from the estimated Kd and the nondisplaceable distribution volume (VND). Results: 11C-UCB-J was synthesized with greater than 98% purity. 11C-UCB-J exhibited high free fraction (0.46 ± 0.02) and metabolized at a moderate rate (39% ± 5% and 24% ± 3% parent remaining at 30 and 90 min) in plasma. In the monkey brain, 11C-UCB-J displayed high uptake and fast kinetics. VT was high (∼25–55 mL/cm3) in all gray matter regions, consistent with the ubiquitous expression of SV2A. Preblocking with 10 and 30 mg/kg of levetiracetam resulted in approximately 60% and 90% occupancy, respectively. Analysis of the self-blocking scans yielded a Kd estimate of 3.4 nM and Bmax of 125–350 nM, in good agreement with the in vitro inhibition constant (Ki) of 6.3 nM and regional Bmax in humans. Whole-body biodistribution revealed that the liver and the brain are the dose-limiting organs for males and females, respectively. Conclusion: 11C-UCB-J exhibited excellent characteristics as an SV2A PET radiotracer in nonhuman primates. The radiotracer is currently undergoing first-in-human evaluation.