PET imaging of adenosine A(1) receptors with (11)C-MPDX as an indicator of severe cerebral ischemic insult.
We examined whether measurement of the adenosine A(1) 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-(11)C]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 (15)O-labeled water, MPDX, (11)C-flumazenil (FMZ), and (18)F-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 (18)F-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 (18)F-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.


CONCLUSIONS
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.
Nariai
Tadashi
T
Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan. nariai.nsrg@tmd.ac.jp
Shimada
Yuhei
Y
Ishiwata
Kiichi
K
Nagaoka
Tsukasa
T
Shimada
Junichi
J
Kuroiwa
Toshihiko
T
Ono
Ken-Ichiro
K
Ohno
Kikuo
K
Hirakawa
Kimiyoshi
K
Senda
Michio
M
D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D002415:Cats; D002560:Cerebrovascular Circulation; D008279:Magnetic Resonance Imaging; D043682:Receptor, Adenosine A1 / Q000032:analysis*; D014055:Tomography, Emission-Computed; D014970:Xanthines / Q000378:metabolism*
C451639:1-methyl-8-dicyclopropylmethyl-1-methyl-3-propylxanthine; D002250:Carbon Radioisotopes; D043682:Receptor, Adenosine A1; D014970:Xanthines