PET imaging of metabotropic glutamate receptor subtype 1 in the ischemic rat brain using 11C-ITMM

Objectives Recent studies have shown the change of metabotropic glutamate receptor subtype 1 (mGluR1) expression in the ischemic brain. We have developed a useful PET ligand 11C-ITMM for imaging mGluR1 in human brain. The aim of this study is to visualize mGluR1 in the ischemic rat brain using PET with 11C-ITMM for the first time.

Methods 11C-ITMM was prepared by reacting its desmethyl precursor with [11C]CH3I. An infarction model of rat brain was prepared by ischemic surgery and used. Small-animal PET imaging with 11C-ITMM was performed for the rats at 2-7 days after the surgery. In vitro autoradiography and immunohistochemical staining were used to support the results of PET study.

Results Compared to the brain without surgery, PET with 11C-ITMM showed a time-dependent decrease of radioactivity accumulation in the ipsilateral side of rat brain at 2, 4, 7 days after the surgery. At 7 days after the surgery, the uptake ratios of ipsilateral to contalateral sides in the same brain sections at 60 min after the radioligand injection were 0.72 ± 0.03 for the striatum and 0.82 ± 0.15 for the cerebral cortex. At 7 days after the surgery and treatment by daily injection of minocycline, a neuroprotective agent, the uptakes ratios between the ipsilateral and contralateral sides returned to 0.86 ± 0.08 for the striatum and 0.95 ± 0.03 for the cerebral cortex. Pretreatment experiment with mGluR1-selective JNJ16259685 reduced the brain uptake significantly, indicating high specific binding of 11C-ITMM reflective to mGluR1 in the brain regions including the infarcted areas. In vitro autoradiography and immunohistochemical assay confirmed the presence of mGluR1 in the ischemic brain, which supported the corresponding PET results.

Conclusions 11C-ITMM PET is a useful biomarker for characterizing the change of mGluR1 expression on the occurrence and progress of infarction and evaluating therapeutic efficiency of drugs for infarction.