Yamasaki, Tomoteru  ,  Fujinaga, Masayuki  ,  Yui, Joji  ,  Wakizaka, Hidekatsu  ,  Ohya, Tomoyuki  ,  Nengaki, Nobuki  ,  Ming-Rong, Zhang

Objectives: Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial target in the developments of new pharmaceuticals to treat central nervous system (CNS) disorders, such as Parkinson’s disease, stroke, and epilepsy. We recently developed N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl-4-[11C]methoxy-N-methylbenzamide ([11C]ITMM) as a potential PET probe for mGluR1 imaging. The aim of this study was to improve visualization and specific binding for mGluR1 using [11C]ITMM with ultra-high specific activity (SA) in small-animal PET studies.Results and Discussion:1. Radiosynthesis of [11C]ITMM: Radiosynthesis for [11C]ITMM, with either conventional or ultra-high SA, was performed by reacting a phenol precursor with [11C]CH3I. For the conventional SA, 1.4–2.8 GBq of [11C]ITMM was produced with 27 ± 5% radiochemical yield at 27 ± 3 min after the end of bombardment (EOB) starting from 14–20 GBq of [11C]CO2. The radiochemical purity was higher than 99% and SA was 121 ± 17 GBq/μmol at the end of synthesis (EOS). For the ultra-high SA, [11C]CH3I was obtained using the single-pass I2 method by iodination of [11C]CH4 which was formed in the target chamber in situ. Starting from 27 GBq of [11C]CH4, 0.7−1.5 GBq of [11C]ITMM was acquired with 6 ± 1% radiochemical yield within 32 min from EOB. The radio chemical purity was higher than 99% and SA was 5,794 ± 1,022 GBq/μmol at EOS.2. Small-animal PET study: Amount of nonradioactive carrier contained in [11C]ITDM with conventional or ultra-high SA was 513.1 ± 58.7 or 10.9 ± 1.6 pmol in the injected solutions for PET studies. In PET images of rat brain with [11C]ITMM of either conventional and ultra-high SA, the highest radioactive accumulation was seen in the cerebellum and the moderates were detected in the thalamus, hippocampus, striatum, and cingulate cortex. The maximum uptake of radioactivity of [11C]ITMM with the conventional and ultra-high SA was 3.0 and 3.4 in the cerebellum, 2.3 and 1.6 in the thalamus, 2.0 and 2.2 in the hippocampus, 2.1 and 2.4 in the striatum, and 2.0 and 2.3 SUV in the cingulate cortex, respectively. To ensure kinetic analysis in PET study, estimations of the equilibrium state of [11C]ITMM with conventional and ultra-high SA in each brain region of interest were obtained using plasma input function and averaged tissue time-activity curves (tTAC). The estimated equilibrium times of [11C]ITMM with conventional and ultra-high SA were 150 and 150 for the cerebellum, 120 and 140 for the thalamus, 120 and 130 for the hippocampus, 120 and 130 for the striatum, and 100 and 120 min for the cingulate cortex, respectively. The uptake of [11C]ITMM with either conventional and ultra-high SA reached at more than 85% of equilibrium state during PET scanning for 90 min.Taken together, uptake of [11C]ITMM with ultra-high SA increased overall compared to the conventional SA, which reached at estimated equilibrium state 90 min after PET scan started. . Kinetic analysis: Kinetic analysis of [11C]ITMM was performed by two-tissue compartment model using plasma input and tTACs. Comparing kinetic parameters between the two SAs, there were no differences in K1 of any brain regions. Meanwhile, k2 and k3 rate constants in the ultra-high SA tended to be faster compared with conventional SA. On the other hand, k4 rate constant in ultra-high SA was slower than in the conventional SA. Correspondingly, distribution volume (VT) and nondisplacable binding potential (BPND) in the ultra-high SA condition were higher than in the conventional SA.The parametric images according to VT scale for [11C]ITMM with the ultra-high SA could be more visualize in mGluR1-rich regions than with the conventional SA and were also possible to identify in mGluR1-poor region, such as substantia nigra. Conclusions: [11C]ITMM with ultra-high SA demonstrated improvement of specific binding for mGluR1 in brain regions. Hence, in vivo monitoring of mGluR1 by PET using [11C]ITMM with ultra-high SA would help further understanding about CNS disorders involved in slight changes of not only mGluR1-rich but also mGluR1-poor regions.
Ninth Japan-China Joint Seminar on Radiopharmaceutical Chemistry

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