Songye Li1, Zhengxin Cai2, Wenjie Zhang3, Daniel Holden4, Shu-Fei Lin4, Sjoerd J Finnema4, Anupama Shirali4, Jim Ropchan4, Stephane Carre5, Joel Mercier5, Richard E Carson4, Nabeel Nabulsi4, Yiyun Huang4. 1. PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06520, USA. songye.li@yale.edu. 2. PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06520, USA. jason.cai@yale.edu. 3. Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China. 4. PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06520, USA. 5. UCB Biopharma, Braine-l'Alleud, Belgium.
Abstract
PURPOSE: Synaptic abnormalities have been implicated in a variety of neuropsychiatric disorders, including epilepsy, Alzheimer's disease, and schizophrenia. Hence, PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) may be a valuable in vivo biomarker for neurologic and psychiatric diseases. We previously developed [11C]UCB-J, a PET radiotracer with high affinity and selectivity toward SV2A; however, the short radioactive half-life (20 min for 11C) places some limitations on its broader application. Herein, we report the first synthesis of the longer-lived 18F-labeled counterpart (half-life: 110 min), [18F]UCB-J, and its evaluation in nonhuman primates. METHODS: [18F]UCB-J was synthesized from the iodonium precursors. PET imaging experiments with [18F]UCB-J were conducted in rhesus monkeys to assess the pharmacokinetic and in vivo binding properties. Arterial samples were taken for analysis of radioactive metabolites and generation of input functions. Regional time-activity curves were analyzed using the one-tissue compartment model to derive regional distribution volumes and binding potentials for comparison with [11C]UCB-J. RESULTS: [18F]UCB-J was prepared in high radiochemical and enantiomeric purity, but low radiochemical yield. Evaluation in nonhuman primates indicated that the radiotracer displayed pharmacokinetic and imaging characteristics similar to those of [11C]UCB-J, with moderate metabolism rate, high brain uptake, fast and reversible binding kinetics, and high specific binding signals. CONCLUSION: We have accomplished the first synthesis of the novel SV2A radiotracer [18F]UCB-J. [18F]UCB-J is demonstrated to be an excellent imaging agent and may prove to be useful for imaging and quantification of SV2A expression, and synaptic density, in humans.
PURPOSE: Synaptic abnormalities have been implicated in a variety of neuropsychiatric disorders, including epilepsy, Alzheimer's disease, and schizophrenia. Hence, PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) may be a valuable in vivo biomarker for neurologic and psychiatric diseases. We previously developed [11C]UCB-J, a PET radiotracer with high affinity and selectivity toward SV2A; however, the short radioactive half-life (20 min for 11C) places some limitations on its broader application. Herein, we report the first synthesis of the longer-lived 18F-labeled counterpart (half-life: 110 min), [18F]UCB-J, and its evaluation in nonhuman primates. METHODS: [18F]UCB-J was synthesized from the iodonium precursors. PET imaging experiments with [18F]UCB-J were conducted in rhesus monkeys to assess the pharmacokinetic and in vivo binding properties. Arterial samples were taken for analysis of radioactive metabolites and generation of input functions. Regional time-activity curves were analyzed using the one-tissue compartment model to derive regional distribution volumes and binding potentials for comparison with [11C]UCB-J. RESULTS: [18F]UCB-J was prepared in high radiochemical and enantiomeric purity, but low radiochemical yield. Evaluation in nonhuman primates indicated that the radiotracer displayed pharmacokinetic and imaging characteristics similar to those of [11C]UCB-J, with moderate metabolism rate, high brain uptake, fast and reversible binding kinetics, and high specific binding signals. CONCLUSION: We have accomplished the first synthesis of the novel SV2Aradiotracer [18F]UCB-J. [18F]UCB-J is demonstrated to be an excellent imaging agent and may prove to be useful for imaging and quantification of SV2A expression, and synaptic density, in humans.
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