Transmesenteric Hernia
Authors: W. V. Beach
Journal: BMJ (1946)

<b>2849</b> <h3><b>Introduction:</b></h3> Glutamate is an important neurotransmitter in the central nervous system that regulated by both ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs can be categorized into three subgroups, groups I to III, according to their sequence homology, pharmacology, and signal transduction mechanism. The mGluR2 and mGluR3 belong to group II mGluRs that negatively modulate the activity of adenylyl cyclase. The mGluR3 is involved in a range of neurological and psychiatric disorders, such as bipolar affective disorder and schizophrenia. To date, there are few reports of selective PET ligands for mGluR3. Herein we report the synthesis and preliminary evaluation of [<sup>18</sup>F]VU6010572 as a novel potential PET ligand for imaging mGluR3 based on the lead molecule developed by Vanderbilt University. <h3><b>Methods:</b></h3> Compound VU6010572 is a negative allosteric modulator (NAM) towards mGluR3 and it has a high mGluR3/mGluR2 selectivity (&gt;100).<sup>1</sup> Compound VU6010572 was prepared and its potency towards mGluR3 was determined by our in house cAMP assay. The radiosynthesis of [<sup>18</sup>F]VU6010572 was performed by copper-mediated <sup>18</sup>F-fluorination of pinacol boronate ester (BPin) precursor with [<sup>18</sup>F]Et<sub>4</sub>NF in DMA/<i>n</i>BuOH at 110 <sup>o</sup>C for 20 min. Dynamic PET imaging studies [<sup>18</sup>F]VU6010572 were carried out on CD-1 mice with 60 min scans. <h3><b>Results:</b></h3> Compound VU6010572 was prepared in 37% overall yield over three steps. The IC<sub>50</sub> value of compound VU6010572 towards mGluR3 was 40 nM in cAMP assay. The pinacol boronate ester (BPin) precursor was prepared in 20% overall yield over four steps. The radiosynthesis of [<sup>18</sup>F]VU6010572 was achieved in 48% isolated radiochemical yield (decay corrected). And [<sup>18</sup>F]VU6010572 has a radiochemical purity (&gt; 99%) and a high molar activity (&gt; 59 GBq/&amp;micro;mol (1.6 Ci/&amp;micro;mol)) at the end of synthesis (EOS). In PET imaging of CD-1 mice, the standard uptake value (SUV) of [<sup>18</sup>F]VU6010572 in the brain reached its max value of 2.5 at 1 min and washed out rapidly, then reduced to 0.4 at 60 min. Pretreatment with compound VU6010572 (3 mg/kg) led to a moderate decrease of bound activity in the brain, and the SUV was reduced by 13% at 45 min with blood correction. <h3><b>Conclusions:</b></h3> We have developed [<sup>18</sup>F]VU6010572 as a novel PET ligand for imaging mGluR3. Compound VU6010572 has a reasonably high potency (IC<sub>50</sub> = 40 nM) towards mGluR3 and [<sup>18</sup>F]VU6010572 could be prepared in high radiochemical yield (48%, decay corrected) with high molar activity (higher than 59 GBq/&amp;micro;mol (1.6 Ci/&amp;micro;mol)). &amp;nbsp;In vivo PET imaging with [<sup>18</sup>F]VU6010572 demonstrated&amp;nbsp; reasonable binding affinities towards mGluR3 and rapid clearance from the brain. Further medicinal chemistry optimization towards higher binding affinity and high specific binding based on [<sup>18</sup>F]VU6010572 scafflod is necessary to identify a suitable PET ligand for mGluR3 imaging.