title: 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, (3)H-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 (11)C-(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 (11)C-(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).
  
  
  CONCLUSIONS
  Zymosan-induced microglial activation and its response to minocycline can be quantitatively imaged in the rat brain using (11)C-(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).
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA. akconverse@wisc.edu
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Converse
authors.forename: Eric C
authors.initials: EC
authors.lastname: Larsen
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Engle
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nickles
authors.forename: Ian D
authors.initials: ID
authors.lastname: Duncan
mesh_terms: D000577:Amides / Q000493:pharmacokinetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004396:Coloring Agents; D005260:Female; D007091:Image Processing, Computer-Assisted; D007249:Inflammation / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000473:pathology; D007536:Isomerism; D007546:Isoquinolines / Q000493:pharmacokinetics; D008262:Macrophage Activation; D017628:Microglia / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology*; D015233:Models, Statistical; D016612:Paraffin Embedding; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015054:Zymosan
chemical_list: C504060:(R)-(11C)1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; D000577:Amides; D000893:Anti-Inflammatory Agents; D004396:Coloring Agents; D007546:Isoquinolines; D019275:Radiopharmaceuticals; D015054:Zymosan; D008911:Minocycline