Abstract
BackgroundMetabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. In the present study, we synthesized [11C]MMPIP, a putative radioligand for mGlu7 (binding constant KB = 30 nM), and evaluated its potential for imaging of mGlu7 via in vitro and in vivo techniques.Methods[11C]MMPIP was synthesized by the reaction of phenol precursor 3 with [11C]CH3I. In vitro autoradiography using [11C]MMPIP was performed on rat brain sections. To determine in vitro specific binding of [11C]MMPIP with mGlu7, a blocking study was conducted by co-incubation with excess AMN082, a selective antagonist for mGlu7, or unlabeled MMPIP. Positron emission tomography (PET) studies and ex vivo metabolite analysis were carried out on rat brains.Results[11C]MMPIP was obtained with two specific activity (SA) levels of average 58 (conventional) and 3,800 (high SA) GBq/μmol, respectively. High radioactive signals derived from conventional [11C]MMPIP in the in vitro autoradiography were seen in the thalamus, medulla oblongata, and striatum, corresponding with comprehensive brain distributions of mGlu7. Co-incubation with ANM082 or unlabeled MMPIP reduced the radioactive signals in the brain sections, respectively. In the PET studies with [11C]MMPIP, no specific uptake relative to mGlu7 was found in the examined brain regions.ConclusionDespite in vitro specific binding of [11C]MMPIP with mGlu7, visualization of mGlu7 in the living brain using PET was not successful. Development of new ligand candidates with higher affinity for mGlu7 is necessary.
Highlights
Metabotropic glutamate 7 receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders
[11C]MMPIP with two different specific activity (SA) levels was synthesized by O-[11C]methylation of precursor 3 with [11C]
MMPIP with 590 ± 80 MBq (n = 5) as an injectable solution of sterile normal saline at the end of synthesis (EOS), starting from [11C]CO2 of 19 ± 4 GBq, which was produced by 12- to 15-min proton (14.2 MeV on target) bombardment using a beam current of 15 μA
Summary
Metabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. Glutamate is a dominant neurotransmitter in the mammalian central nervous system (CNS), inducing excitatory neurotransmission by binding to its receptors. Eight subtypes of metabotropic glutamate receptors (mGlu to 8) have been identified and divided into three groups based on sequence homology, pharmacology, and coupling pathway to G. Of the group III receptors, mGlu is mainly localized on the presynaptic terminals of glutamatergic neurons, and its signaling pathways are activated only under conditions of emergency synaptic activity because of its low affinity to glutamate [7]. Studies on mGlu7-deficient mice have directly demonstrated that mGlu plays the most important role in controlling neuronal excitability via feedback regulation of glutamate in the synaptic cleft [8]. Recent advances in the generation of transgenic animals and the identification of selective or specific ligands have revealed important insights into the potential role of mGlu in the pathophysiology of neurological disorders [10,11]
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