TY - JOUR T1 - Synthesis and characterization of [<sup>18</sup>F]mG2P018 as the first efficient <sup>18</sup>F-labeled PET imaging ligand for metabotropic glutamate receptor 2 JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 266 LP - 266 VL - 61 IS - supplement 1 AU - Gengyang Yuan AU - Chuzhi Pan AU - Xiying Qu AU - Anna-Liisa Brownell Y1 - 2020/05/01 UR - http://jnm.snmjournals.org/content/61/supplement_1/266.abstract N2 - 266Objectives: Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders. Development of specific PET imaging ligand is important to elucidate the pathophysiological mechanism involved in mGluR2 function. We have previously developed [11C]mG2P001 as a PET radioligand for imaging mGluR2 in the brain. However, the short half-life of carbon-11 (20.4 min) will limit its broader application. Here, we describe the [18F]mG2P018, a mGluR2 positive allosteric modulator (PAM), as a mGluR2-specific PET imaging ligand through a comprehensive in vivo characterization in mice, rats and nonhuman primates (NHPs). Methods: [18F]mG2P018 was prepared via a copper (I)-mediated radiofluorination of aryl boronic pinacol ester. The radiosynthetic procedure was modified to tolerate the presence of labile heterocyclic group and be applied in the GE TRACERLabTM FXF-N radiosynthetic module. In vivo PET imaging experiments with [18F]mG2P018 were conducted at first in C57BL/6J mice and Sprague-Dawley rats to obtain its whole-body biodistribution and brain uptake profile. Subsequent PET studies in Cynomolgus monkeys provided further evaluation of [18F]mG2P018 on its uptake in different brain areas as well as its metabolism and pharmacokinetic properties. Blocking experiments were carried out by using self-blocking with mG2P018 in rats as well as blockade with mG2P001 in both rats and monkeys to assess the pharmacological effects of [18F]mG2P018. Arterial blood samples from monkeys were drawn for analysis of radioactive metabolites in plasma and generation of metabolite-corrected arterial plasma input functions for kinetic modeling and quantitative analyses. Regional time-activity curves (TACs) were analyzed via a reversible two-compartment model and Logan plot to produce reliable regional total volume of distribution (VT) estimates. Results: [18F]mG2P018 was obtained with satisfactory radiochemical yield (RCY = 10 ± 4%, n &gt; 10, non-decay corrected), excellent radiochemical purity (&gt; 95%) and high molar activity (180 ± 102 GBq/µmol). [18F]mG2P018 demonstrated reversible kinetic accumulating in all tissue areas and a combined renal and hepatobiliary clearance in mice. In rats, [18F]mG2P018 accumulated in mGluR2-rich regions of cortex, striatum, thalamus and cerebellum with a peak brain uptake of 3.7 ± 0.7 (SUV) at 3 min in the thalamus. The brain uptake of [18F]mG2P018 was reduced by pre-administration of mG2P018 and mG2P001 by around 5-15% and 20-40%, respectively. The following monkey studies further confirmed this observation and a reduction of about 10-15% radioactivity was seen via mG2P001 blocking at a dose of 1 mg/kg. The two-tissue compartment model was confirmed as a suitable model for analyzing the regional distribution of [18F]mG2P018 with arterial plasma input function. VTs estimated with Logan graphical method were in good agreement with those obtained by full compartment analysis. TACs in different brain regions also demonstrated reversible kinetics in monkeys. Conclusions: We have developed [18F]mG2P018 as the first efficient fluorine-18 labeled PET imaging ligand for mGluR2. The radiosynthesis of [18F]mG2P018 was achieved with automated GE TRACERLabTM FXF-N system under the modified protocol. [18F]mG2P018 demonstrated satisfactory imaging results in both rodent and monkey studies, thus warrants its further investigation for translational studies. Acknowledgements: The research was supported by NIH grants R01EB021708 and R01NS100164. ER -