Synthesis and evaluation of 1-(cyclopropylmethyl)-4-(4-[ 11 C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([ 11 C]CMDC) for PET imaging of metabotropic glutamate receptor 2 in the rat brain

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

“…In the baseline study, the distribution of bound radioactivity was heterogeneous with signal levels from high to low in the order of cerebral cortex, striatum, hippocampus, cerebellum and pons/medulla (Figure 5B). These autographic results are in agreement with both the previously published distribution of mGlu 2 in rat brain, 10,12 and with other autoradiography studies with the mGlu 2 radioligands [ 11 C]CMDC, 51 [ 3 H]JNJ-40068782, 54 [ 3 H]LY341495 71 and [ 3 H]LY459477. 14 As shown in Figure 5C, quantitative analysis of radioactivity binding in the mGlu 2 -rich regions (cerebral cortex, striatum, hippocampus and cerebellum) with unlabeled QCA (1 µM) and a NAM MNI-137 61 (1 µM) showed ca.…”

“…The radioactivity was efficiently cleared from blood (1 min/60 min ratio of 2.4) and high radioactivity in the liver, kidneys and small intestine indicated urinary and hepatobiliary excretion, as well as a possible intestinal reuptake pathway. The distribution of [ 11 C]QCA in the peripheral organs was similar to prior reports with other compounds, 51,56,69,70 in which rapid clearance of radioactivity from heart, lungs, spleen and muscle was observed. Limited brain uptake (peak value 0.42% ID/g at 1 min post injection) was observed, and thus the regional brain distribution was further studied by in vitro autoradiography.…”

“…0.6 SUV). 51 Preliminary evaluation in PET imaging studies for compounds 3 , 5 , 6 are not yet disclosed for the development of mGlu 2 tracers. 52,53 Only two PET tracers, namely [ 11 C]JNJ-42491293 ( 2 ) and a 11 C-compound from Merck, have been advanced to first-in-human studies.…”

A Review of Molecular Imaging of Glutamate Receptors

“…Evaluations in rats showed only a hint of displaceable binding ex vivo, due to the tracer’s poor permeability to the BBB, which the authors attributed to hindering effects of the carboxylic acid moiety [ 206 ]. Ma et al reported the radiosynthesis of 1-(cyclopropylmethyl)-4-(4-[ 11 C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([ 11 C]CMDC, 89 ) for the PET imaging of mGluR2 [ 207 ]. The compound is a methoxy-analogue of the compound JNJ-40068782, with a K D value of 10 nM for recombinant human mGluR2 in vitro [ 208 ].…”

Synthesis and preliminary studies of 11C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2

“…Furthermore, the development of high-affinity and selective mGlu 2 PET tracers would enable clinical translation of mGlu 2 modulators by providing a means to perform target engagement and dose occupancy studies. In the past several years, continuous research efforts have been invested in the development of PET ligands for imaging mGlu 2 , including [ 11 C]CMG ( 1 ) 41 , [ 11 C]CMGDE ( 2 ) 41 , [ 11 C]JNJ42491293 ( 3 ) 42 , [ 18 F]FE-JNJ42491293 ( 4 ) 43 , [ 11 C]CMDC ( 5 ) 44 , and our recently reported PET ligands namely [ 11 C]QCA ( 6 ) 45 and [ 11 C]MMP ( 7 ) 46 ( Figure 1 ). As the first studied mGlu 2 PET tracer, [ 11 C]CMG ( 1 ) failed to cross blood-brain-barrier (BBB), which was then overcome by its ester derivative [ 11 C]CMGDE ( 2 ) 41 .…”