Monitoring neuroprotective effects using positron emission tomography with [11C]ITMM, a radiotracer for metabotropic glutamate 1 receptor.

Abstract

BACKGROUND AND PURPOSE:

Recent pharmacological evidence shows that antagonists for the metabotropic glutamate 1 (mGlu1) receptor exhibit neuroprotective effects in an ischemic brain. The aim of this study was to visualize the mGlu1 receptor and to monitor neuroprotective effects in a rat model of mild focal ischemia using positron emission tomography (PET) with N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]ITMM), a radiotracer for mGlu1.

METHODS:

Rats were subjected to a 30-minute transient right middle cerebral artery occlusion. Saline or minocycline, a neuroprotective agent, was intravenously injected immediately after surgery and then daily during the subsequent 7 days. PET imaging with [(11)C]ITMM was performed on the rats on days 1 to 7 after ischemia. In vitro autoradiography and histopathologic staining were conducted to confirm the results of in vivo PET.

RESULTS:

PET with [(11)C]ITMM demonstrated a gradual decrease of radioactivity in the ipsilateral sides of the ischemic brains. The radioactivity uptake ratio between the ipsilateral and contralateral sides also decreased with time. Minocycline treatment slowed down the decrease in the radioactivity level in the ipsilateral sides. Pretreatment with JNJ16259685, an mGlu1-selective ligand, significantly reduced brain radioactivity, confirming that the uptake of [(11)C]ITMM primarily reflects mGlu1 levels in the brain regions, including the ischemic area. In vitro autoradiography and histopathology confirmed the changes in mGlu1 levels in the brains.

CONCLUSIONS:

[(11)C]ITMM-PET may be a useful technique for characterizing the change in mGlu1 level during the occurrence and progression of neuronal damage and for evaluating the neuroprotective effects of drugs after ischemia.

• Authors: Joji Yui, Lin Xie, Masayuki Fujinaga, Tomoteru Yamasaki, Akiko Hatori, Katsushi Kumata, Nobuki Nengaki, Ming-Rong Zhang
• Journal: Stroke (Stroke) Vol. 44 Issue 9 Pg. 2567-72 (Sep 2013) ISSN: 1524-4628 [Electronic] United States
• PMID: 23908068 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Carbon Radioisotopes
• Ligands
• N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide
• Neuroprotective Agents
• Radiopharmaceuticals
• Receptors, Metabotropic Glutamate
• Thiazoles
• metabotropic glutamate receptor type 1
• Minocycline
• N-methylbenzamide

Topics

• Animals
• Benzamides (pharmacology)
• Carbon Radioisotopes
• Disease Models, Animal
• Infarction, Middle Cerebral Artery (complications, etiology, metabolism)
• Ligands
• Male
• Minocycline (administration & dosage, pharmacology)
• Neuroprotective Agents (administration & dosage, pharmacology)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, drug effects, metabolism)
• Thiazoles