Abstract
Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial target in the development of new medications to treat central nervous system (CNS) disorders. Recently, we developed N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[11C]methoxy-N-methyl-benzamide ([11C]ITMM) as a useful positron emission tomography (PET) probe for mGluR1 in clinical studies. Here, we aimed to improve visualization and threshold of specific binding for mGluR1 using [11C]ITMM with ultra-high specific activity (SA) of > 3,500 GBq/μmol in rat brains. A two-tissue compartment model indicated large differences between the two SAs in the constants k3 and k4, representing binding ability for mGluR1, while constants K 1 and k2 showed no differences. The total distribution volume (VT) values of conventional and ultra-high SA were 9.1 and 11.2 in the thalamus, 7.7 and 9.7 in the striatum, and 6.4 and 8.5 mL/cm3 in the substantia nigra, respectively. The specific binding of [11C]ITMM with ultra-high SA was significantly higher than the conventional SA, especially in the basal ganglia. Parametric PET images scaled with VT of the ultra-high SA clearly identified regional differences in the rat brain. In conclusion, PET studies using [11C]ITMM with ultra-high SA could sufficiently improve visualization and specific binding for mGluR1, which could help further understanding for mGluR1 functions in CNS disorders.
Highlights
Glutamate is a major neurotransmitter that triggers excitatory neurotransmission via receptor binding in the central nervous system (CNS)
The Metabotropic glutamate receptors (mGluRs) subtype 1 categorized in group I is coupled with Gq proteins and can stimulate polyphosphoinositide hydrolysis, resulting in the formation of the second messengers inositol 1, 4, 5-triphosphate and diacylglycerol
The radiochemical purity was higher than 99% and 121 ± 17 GBq/μmol of specific activity (SA) was obtained at the end of synthesis (EOS). [11C]ITMM with ultra-high SA was synthesized with 6 ± 1% radiochemical yield
Summary
Glutamate is a major neurotransmitter that triggers excitatory neurotransmission via receptor binding in the central nervous system (CNS). PET Study Using [11C]ITMM with Ultra-High SA coupled receptors. They can be classified into three groups comprising eight subtypes, based on sequence homology, intracellular transduction pathways, and pharmacological properties [1, 2]. The mGluR subtype 1 (mGluR1) categorized in group I is coupled with Gq proteins and can stimulate polyphosphoinositide hydrolysis, resulting in the formation of the second messengers inositol 1, 4, 5-triphosphate and diacylglycerol. These messengers trigger intracellular calcium release and activation of protein kinase C [3,4,5]
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