Characterization of fluoromisonidazole binding in stroke

• Published in: Stroke (1970) Vol. 37; no. 7; pp. 1862 - 1867
• Main Authors: SPRATT, Neil J, ACKERMAN, Uwe, TOCHON-DANGUY, Henri J, DONNAN, Geoffrey A, HOWELLS, David W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-07-2006
• Subjects: Animals; Autoradiography - methods; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Brain - pathology; Cell Hypoxia; Cerebrovascular Circulation; Contrast Media - pharmacokinetics; Fluorine Radioisotopes - pharmacokinetics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hypoxia, Brain - diagnostic imaging; Hypoxia, Brain - etiology; Hypoxia, Brain - pathology; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - diagnostic imaging; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Laser-Doppler Flowmetry; Medical sciences; Misonidazole - analogs & derivatives; Misonidazole - analysis; Misonidazole - pharmacokinetics; Nervous system (semeiology, syndromes); Neurology; Pharmacology. Drug treatments; Positron-Emission Tomography; Protein Binding; Radioactive Tracers; Rats; Rats, Sprague-Dawley; Reperfusion; Time Factors; Vascular diseases and vascular malformations of the nervous system; Animal model; Cerebral infarction; acute; Stroke; Nervous system diseases; animal models; pathology; Cardiovascular disease; Cerebral disorder; Vascular disease; Anatomic pathology; Central nervous system disease; Cerebrovascular disease
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.str.0000226908.93295.9d

[18F]fluoromisonidazole (FMISO) positron emission tomography has been used to image hypoxia early after human stroke. To further study the role of hypoxia in stroke and the binding characteristics of FMISO, we aimed to develop [3H]FMISO autoradiography in an animal stroke model. We hypothesized that [3H]FMISO binding is prolonged, allowing correlation with 24-hour histology, and that there is no FMISO binding after effective reperfusion.
Temporary middle cerebral artery (MCA) occlusion was performed in rats, followed by [3H]FMISO administration. Tissue preparation for autoradiography and histology (from the same sections) was performed 2.5 hours after MCA occlusion (MCAo; replicating [18F]FMISO studies). Then, otherwise identical cohorts with tissue preparation at 2.5 or 24 hours were prepared. For reperfusion studies, animals had 1-hour MCAo, with [3H]FMISO administered 1 hour after reperfusion.
[3H]FMISO autoradiography provided a high-resolution image of hypoxia throughout the ischemic territory. Delaying animal death from 2.5 to 24 hours allowed histological changes of stroke to develop, without significantly altering either relative intensity (1.88+/-0.06 and 2.02+/-0.11, respectively) or volume (25+/-6 mm3 and 28+/-5 mm3, respectively) of hypoxic binding. [3H]FMISO binding did not occur after effective reperfusion, despite histological injury from the preceding MCAo.
[3H]FMISO autoradiography of hypoxia in experimental stroke offers several advantages. Bound FMISO is retained in tissues long term, enabling direct correlation with 24-hour histology. It is not bound after effective reperfusion. Therefore, positive [18F]FMISO positron emission tomography studies in stroke patients are indicative of ongoing tissue hypoxia, not merely recent tissue injury.