Imaging of brain hypoxia in permanent and temporary middle cerebral artery occlusion in the rat using 18F-fluoromisonidazole and positron emission tomography:: a pilot study

In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. Previous human studies using F-18-fluoromisonidazole and positron emission tomography (F-18-FMISO PET) have shown high tracer retention indicative of tissue hypoxia, which had normalized at repeat scan > 48 h later. In the only validation study of F-18-FMISO, using ex vivo autoradiography in thread middle cerebral artery occluded (MCAo) rats, there was unexpected high uptake as late as 22 h after reperfusion, raising questions about the use of F-18-FMISO as a hypoxia tracer. Here we report a pilot study of F-18-FMISO PET in experimental stroke. Spontaneous hypertensive rats were subjected to distal clip MCAo. Three-hour dynamic PET was performed in 7 rats: 3 normals, 1 with permanent MCAo (two sessions: 30 mins and 48 h after clip), and 3 with temporary MCAo (45 mins, n = 1; 120 mins, n = 2; scanning started 30 mins after clip removal). Experiments were terminated by perfusion-fixation for standard histopathology. Late tracer retention was assessed by both compartmental modelling and simple side-to-side ratios. In the initial PET session of the permanent MCAo rat, striking trapping of F-18-FMISO was observed in the affected cortex, which had normalized 48 h later; histopathology revealed pannecrosis. In contrast, there was no demonstrable tracer retention in either temporary MCAo models, and histopathology showed ischemic changes only. These results document elevated F-18-FMISO uptake in the stroke area only in the early phase of MCAo, but not after early reperfusion nor when tissue necrosis has developed. These findings strongly support the validity of F-18-FMISO as a marker of viable hypoxic tissue/penumbra after stroke.