Author: Korat, Špela ; Munoz-Sanjuan, Ignacio ; Staelens, Steven ; Miranda, Alan ; Verhaeghe, Jeroen ; Dominguez, Celia ; Skinbjerg, Mette ; Wyffels, Leonie ; Mrzljak, Ladislav ; Stroobants, Sigrid ; Bertoglio, Daniele ; Liu, Longbin

AbstractPurposeThis study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [11C]ITDM in mice.ProceduresWe performedin vivoblocking as well as displacement of [11C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessedin vitroblocking of [3H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [11C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches.ResultsIn vivoblocking with YM-202074 resulted in a decreased [11C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition,in vitro[3H]ITDM binding could be blocked in a dose-dependent manner. The volume of distribution (VT) based on the noninvasive IDIF (VT (IDIF)) showed excellent agreement with theVTvalues based on the metabolite-corrected plasma input function regardless of the metabolite correction (r2 > 0.943,p < 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r2 > 0.960,p < 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r2 = 0.379,p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach.ConclusionsNo suitable reference region could be identified for [11C]ITDM as strongly supported byin vivoandin vitroevidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [11C]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain.

01 Jul 2010·Nuclear Medicine and BiologyQ4 · MEDICINE

Radiosynthesis and evaluation of [11C]YM-202074 as a PET ligand for imaging the metabotropic glutamate receptor type 1

Q4 · MEDICINE

Article

Author: Nengaki, Nobuki ; Yamasaki, Tomoteru ; Konno, Fujiko ; Wakizaka, Hidekatsu ; Kawamura, Kazunori ; Zhang, Ming-Rong ; Odawara, Chika ; Takei, Makoto ; Yanamoto, Kazuhiko ; Hatori, Akiko ; Yui, Joji

INTRODUCTIONDeveloping positron emission tomography (PET) ligands for imaging metabotropic glutamate receptor type 1 (mGluR1) is important for studying its role in the central nervous system. N-cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074) exhibited high binding affinity for mGluR1 (K(i)=4.8 nM), and selectivity over other mGluRs in vitro. The purpose of this study was to label YM-202074 with carbon-11 and to evaluate in vitro and in vivo characteristics of [(11)C]YM-202074 as a PET ligand for mGluR1 in rodents.METHODS[(11)C]YM-202074 was synthesized by N-[(11)C]methylation of its desmethyl precursor with [(11)C]methyl iodide. The in vitro and in vivo brain regional distributions were determined in rats using autoradiography and PET, respectively.RESULTS[(11)C]YM-202074 (262-630 MBq, n=5) was obtained with radiochemical purity of >98% and specific activity of 27-52 GBq/mumol at the end of synthesis, starting from [(11)C]CO(2) of 19.3-21.5 GBq. In vitro autoradiographic results showed that the high specific binding of [(11)C]YM-202074 for mGluR1 was presented in the cerebellum, thalamus and hippocampus, which are known as mGluR1-rich regions. In ex vivo autoradiography and PET studies, the radioligand was specifically distributed in the cerebellum, although the uptake was low. Furthermore, the regional distribution was fairly uniform in the whole brain by pretreatment with JNJ16259685 (a mGluR1 antagonist). However, radiometabolite(s) was detected in the brain.CONCLUSIONSFrom these results, especially considering the low brain uptake and the influx of radiometabolite(s) into brain, [(11)C]YM-202074 may not be a useful PET ligand for in vivo imaging of mGluR1 in the brain.

01 Jan 2008·Brain ResearchQ4 · MEDICINE

Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models

Q4 · MEDICINE

Article

Author: Atsuyuki Kohara ; Masayasu Takahashi ; Masamichi Okada ; Shigeki Kawabata ; Satoshi Hayashibe ; Shin-ichi Yatsugi ; Yoshitsugu Shitaka ; Seiji Tamura

We describe in vitro properties and in vivo neuroprotective effects of a newly synthesized, high-affinity, selective allosteric metabotropic glutamate receptor type 1 (mGluR(1)) antagonist, N-cyclohexyl-6-{[(2-methoxyethyl)(methyl)amino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074). YM-202074 bound an allosteric site of rat mGluR(1) with a K(i) value of 4.8+/-0.37 nM. YM-202074 also inhibited the mGluR(1)-mediated inositol phosphates production in rat cerebellar granule cells with an IC(50) value of 8.6+/-0.9 nM, while showing selectivity over mGluR(2-7). When YM-202074 was infused intravenously at an initial dose of 20 mg/kg/h for 0.5 h followed by a dose of 5 mg/kg/h for 7.5 h, the free concentration of YM-202074 in the brain rapidly (<12 min) reached approximately 0.3 microM, reaching a steady-state phase within 1.5 h. We first treated rats such that they developed transient middle cerebral artery (MCA) occlusion. Results clearly demonstrate a dose-dependent improvement of neurological deficit and reduction of the infarct volume in both the hemisphere and cortex when YM-202074 was infused intravenously immediately after occlusion at a dose of 10 or 20 mg/kg/h for 0.5 h followed by a dose of 2.5 or 5 mg/kg/h for 23.5 h, respectively. Significant neuroprotection was maintained even when the administration of drugs was delayed by up to 2 h following the onset of ischemia. Furthermore, the improvement of neurological deficit and the reduction of infarct volume were sustained for 1 week following the onset of ischemia. These results suggest that YM-202074 exhibits great potential as a novel neuroprotective agent for the treatment of stroke.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Discovery	JP	Astellas Pharma, Inc.	-

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