Background

[PubMed]

Glutamate is a major excitatory neurotransmitter at neuronal synapses in the central nervous system (CNS) (1, 2). Glutamate produces its excitatory effects by acting on cell-surface ionotropic glutamate or metabotropic glutamate receptors (mGluRs). The mGluRs are GTP-binding protein (G-protein)–coupled receptors that play important roles in regulating the activity of many synapses in the CNS, and many neuronal projection pathways contain mGluRs. There are eight mGluR subtypes, which are further subdivided into groups I, II, and III. The group I receptors include mGluR1 and mGluR5, and they are found predominantly in postsynaptic locations. The mGluR1 is found in moderate to high density in the cerebellum, caudate, putamen, thalamus, cingulate cortex, and hippocampus, with low density in the pons. The mGluR5 is usually found in moderate to high density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, and hippocampus, whereas the density in the cerebellum is low. The mGluR1 and mGluR5 are positively coupled to phospholipase C in the regulation of neuronal excitability (3). Dysfunction of mGluR1 and mGluR5 is implicated in a variety of diseases in the CNS, including anxiety, depression, schizophrenia, Parkinson’s disease, and drug addiction or withdrawal (2, 4).

Positron emission tomography (PET) and single-photon emission tomography of radioligands targeting the mGluR1 can visualize and analyze mGluR1 expression in normal physiological and pathological conditions. Several radioligands have been studied for in vivo imaging of the mGluR1 in the brain (5). 1-(2-Fluoro-3-pyridyl)-4-(2-propyl-1-oxo-isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole (MK-1312) was shown to be selective for the mGluR1, with nanomolar affinity (3.6 nM), and exhibited little inhibition of the mGluR5 (6). Hostetler et al. (6) prepared and evaluated 1-(2-[¹⁸F]fluoro-3-pyridyl)-4-(2-propyl-1-oxo-isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole ([¹⁸F]MK-1312) for use with in vivo PET imaging of mGluR1 distribution in the brain of rhesus monkeys.

Synthesis

[PubMed]

Hostetler et al. (6) reported a one-step automated synthesis of [¹⁸F]MK-1312. The chloro-precursor was subjected to nucleophilic fluorination with K[¹⁸F]F/Kryptofix2.2.2 for 4 min at 120°C, with a radiochemical yield of 46 ± 15% and an average specific activity of 91.39 ± 51.43 GBq/µmol (2.47 ± 1.39 Ci/µmol, n = 25) after purification with high-performance liquid chromatography. The radiochemical purity of [¹⁸F]MK-1312 was >98%. The total synthesis time was ~45 min. MK-1312 exhibited a log P value of 2.3.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro [¹⁸F]MK-1312 autoradiography studies were performed on rhesus monkey and human brain sections (n = 6/group) (6). [¹⁸F]MK-1312 bound heterogeneously to the brain sections of both species, with the highest accumulation of radioactivity in the mGluR1-rich cerebellum, followed by a moderate radioactivity in the hippocampus and thalamus, and with the lowest radioactivity in the cortical regions and caudate/putamen. MK-1312 or MK-5435 (10,000 nM, mGluR1 antagonists) completely blocked radioactive signals to background levels in these brain regions. Saturation binding studies using [¹⁸F]MK-1312 with monkey and human cerebellum and cortex homogenates were performed. The binding potential (BP, B_max/K_d) values were 20 and 132 for the monkey cortex and cerebellum, respectively. The BP values were 24 and 98 for the human cortex and cerebellum, respectively. There was one binding site for the monkey brain homogenates and one for the human brain homogenates, with K_d values of 0.45 ± 0.13 nM and 0.97 ± 0.29 nM, respectively.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

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Abe T., Sugihara H., Nawa H., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J Biol Chem. 1992;267(19):13361–8. [PubMed: 1320017]

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Gasparini F., Lingenhohl K., Stoehr N., Flor P.J., Heinrich M., Vranesic I., Biollaz M., Allgeier H., Heckendorn R., Urwyler S., Varney M.A., Johnson E.C., Hess S.D., Rao S.P., Sacaan A.I., Santori E.M., Velicelebi G., Kuhn R. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology. 1999;38(10):1493–503. [PubMed: 10530811]

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Yamasaki T., Fujinaga M., Yoshida Y., Kumata K., Yui J., Kawamura K., Hatori A., Fukumura T., Zhang M.R. Radiosynthesis and preliminary evaluation of 4-[18F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylb enzamide as a new positron emission tomography ligand for metabotropic glutamate receptor subtype 1. Bioorg Med Chem Lett. 2011;21(10):2998–3001. [PubMed: 21470858]

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Hostetler E.D., Eng W., Joshi A.D., Sanabria-Bohorquez S., Kawamoto H., Ito S., O'Malley S., Krause S., Ryan C., Patel S., Williams M., Riffel K., Suzuki G., Ozaki S., Ohta H., Cook J., Burns H.D., Hargreaves R. Synthesis, characterization, and monkey PET studies of [(1)(8)F]MK-1312, a PET tracer for quantification of mGluR1 receptor occupancy by MK-5435. Synapse. 2011;65(2):125–35. [PubMed: 20524178]