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PET Imaging of Adenosine A₁ Receptors with ¹¹C-MPDX as an Indicator of Severe Cerebral Ischemic Insult

¹ Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan
² Department of Veterinary Clinical Pathobiology, University of Tokyo, Tokyo, Japan
³ Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
⁴ Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan
⁵ Department of Neuropathology, Tokyo Medical and Dental University, Tokyo, Japan

We examined whether measurement of the adenosine A₁ receptor (A1-R) with PET can predict the severity of ischemic brain damage using an occlusion and reperfusion model of the cat middle cerebral artery (MCA) and [1-methyl-¹¹C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX), a positron-emitting radioligand developed at our institution. Methods: Eighteen adult cats underwent PET measurement of cerebral blood flow (CBF), A1-R, central benzodiazepine receptor (BDZ-R), and glucose metabolism with ¹⁵O-labeled water, MPDX, ¹¹C-flumazenil (FMZ), and ¹⁸F-FDG, respectively. The right MCAs of 13 cats were transiently occluded via a transorbital approach with microvascular clips. CBF was measured before occlusion of MCA, during occlusion, and immediately after reperfusion. After CBF measurement, A1-R, BDZ-R, and ¹⁸F-FDG uptake were serially measured in the order listed. Two months later, the degree of ischemic damage was evaluated by T2-weighted MR images obtained with an animal MRI system and by analysis of histologic specimens. Five cats that received no operations were used as controls. Results: The cats that underwent occlusion were divided into 3 groups: cats that did not survive the first day because of severe neurologic and systemic conditions (n = 4), cats that survived and had infarcted lesions in both the cortex and the striatum (n = 3), and cats that survived and had infarcted lesions only in the striatum (n = 6). CBF during occlusion of the MCA was significantly lower in all 3 ischemic groups than in the control group, but there was no significant difference among the ischemic groups. Right-to-left ratios of CBF and ¹⁸F-FDG uptake did not significantly differ among the groups. MPDX binding and FMZ binding were significantly lower in the groups with severe ischemic insult than in the groups with little to no insult. Conclusion: The degree of decreased MPDX binding to A1-Rs after reperfusion was a sensitive predictor of severe ischemic insult. MPDX PET has good potential to become a suitable in vivo imaging technique for evaluating the function of adenosine and A1-Rs in relation to cerebral ischemia.

Key Words: PET • cerebral ischemia • adenosine A₁ receptor • cat • middle cerebral artery occlusion • glucose metabolism

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				N. Fukumitsu, K. Ishii, Y. Kimura, K. Oda, T. Sasaki, Y. Mori, and K. Ishiwata Adenosine A1 Receptor Mapping of the Human Brain by PET with 8-Dicyclopropylmethyl-1-11C-Methyl-3-Propylxanthine J. Nucl. Med., January 1, 2005; 46(1): 32 - 37. [Abstract] [Full Text] [PDF]