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Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, the inhibition of MAGL is an attractive therapeutic target for neurodegenerative diseases. In this study, to visualize MAGL via positron emission tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1 H -pyrazol-3-yl)azetidine-1-[11C]carboxylate ([11C] 6). Compound 6 exhibited high in vitro binding affinity (IC 50 = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [11C] 6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [11C]phosgene ([11C]COCl 2), followed by a reaction with 3-(1-benzyl-1 H -pyrazol-3-yl)azetidine hydrochloride (8), which resulted in a 15.0 ± 6.8% radiochemical yield (decay-corrected, n = 7) based on [11C]CO 2 and a 45 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in MAGL-rich organs, including the lungs, heart, and kidneys. More than 90% of the total radioactivity was irreversibly bound in the brain homogenate of rats 5 min and 30 min after the radiotracer injection. PET summation images of rat brains showed high radioactivity in all brain regions. Pretreatment with 6 or MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. [11C] 6 is a promising PET tracer which offers in vivo specific binding and selectivity for MAGL in rodent brains. [ABSTRACT FROM AUTHOR]

Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3- a ]pyridine (CMTP, 1a). [11C]CMTP ([11C] 1a) was synthesized by O-[11C]methylation of desmethyl precursor 1b with [11C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [11C]CO 2) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [11C] 1a possessed moderate in vitro specific binding to mGluR2 in the rat brain, with a heterogeneous distribution of radioactive accumulation in the mGluR2-rich brain tissue sections, such as the cerebral cortex and striatum. PET study indicated that [11C] 1a was able to cross the blood–brain barrier and enter the brain, but had very low specific binding in the rat brain. Further optimization for the chemical structure of 1a is necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain. [ABSTRACT FROM AUTHOR]

• Efficient radiosynthetic route to a 18F-labeled M4 PET ligand. • High radiochemical yield and high molar activity. • Modest in vitro binding specificity by autoradiography studies. • Limited brain penetration in rodents. Positive allosteric modulators of muscarinic acetylcholine receptor subtype 4 have been identified as promising activators for the treatment of neurological disorders and neurodegenerative diseases, including schizophrenia, Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Herein we report the synthesis and preliminary evaluation of a 18F-labeled positron emission tomography ligand based on a M 4 activator (7). 18F-Isotopologue of 7 was prepared in a reasonable radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed moderate in vitro specific binding. Dynamic PET studies in vivo demonstrated that 18F] 7 (also named as 18F]M 4 R-1911) failed to cross the blood–brain barrier. Therefore, further chemical scaffold optimization in chemotype of 7 is necessary to overcome limited brain permeability and improve specific binding. [ABSTRACT FROM AUTHOR]

Transmembrane AMPA Receptor Regulatory Proteins (TARPs) are a recently discovered family of proteins that modulate the activity of AMPA receptors in the ionotropic glutamate system. TARPs exhibit regional specific expression in the brain, leading to physiological differentiation and modulation of AMPA activity. Herein we develop a novel PET ligand based on a novel TARP subtype γ-8 dependent antagonist and perform preliminary evaluation by PET. Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[ d ]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its 11C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo. [ABSTRACT FROM AUTHOR]