11C-(R)-PK11195 PET imaging of microglial activation and response to minocycline in zymosan-treated rats

Abstract

We sought to advance methodology for studying microglial activation and putative therapeutic downregulation in response to minocycline by means of noninvasive in vivo imaging. A reproducible focal white matter lesion was used to reliably compare treatment conditions. Methods: The corpus callosum of female Sprague Dawley rats was injected with zymosan to promote microglial activation as confirmed by hematoxylin and eosin staining, 3H-PK11195 autoradiography, and CD11b immunohistochemistry. A subset of subjects was treated systemically with minocycline to potentially alter microglial activation. Seven days after zymosan injection, subjects were imaged with PET using the radiotracer 11C-(R)-PK11195. In vivo binding was evaluated using the distribution volume ratio (DVR) with respect to a reference region. Results: At the lesion site, the observed 11C-(R)-PK11195 DVR for each treatment was as follows: mean saline DVR ± SD, 1.17 ± 0.05 (n = 5); zymosan-only DVR, 1.96 ± 0.33 (n = 10); and zymosan with minocycline DVR, 1.58 ± 0.12 (n = 9). Therefore, compared with controls, zymosan increased binding (P = 0.0001, 2-tailed t test) and minocycline treatment reduced zymosan-induced binding by 46% (P = 0.004, 2-tailed t test). Conclusion: Zymosan-induced microglial activation and its response to minocycline can be quantitatively imaged in the rat brain using 11C-(R)-PK11195 PET. The ability to detect a treatment effect in a focal white-matter lesion may be of use in studying therapies for multiple sclerosis (MS). Copyright © 2011 by the Society of Nuclear Medicine, Inc.