A new nitroxyl-probe with high retention in the brain and its application for brain imaging.
In order to estimate free radical reactions and image them in the brain of living animals, a nitroxyl spin-probe, carboxy-PROXYL acetoxymethyl ester (CxP-AM) was newly synthesized. CxP-AM was designed to be hydrolyzed by esterase, but not by lipase, so that it would pass through the blood-brain barrier and be retained in the cytosolic phase of parenchymal cells in the brain after intravenous injection. The pharmacokinetics of CxP-AM was compared with those of carboxy-PROXYL (CxP) and its methyl ester (CxP-M). Carboxyl esterase almost completely hydrolyzed CxP-AM within 3 min. After intravenous injection, the brain retained 1.8 times more CxP-AM than CxP-M, and retained it for more than 30 min. Electron spin resonance computed tomographic (ESR-CT) imaging of CxP-AM in the heads of mice produced marked contrast in the encephalon region, while CxP was distributed only in the extracranial region and CxP-M was distributed in both regions, confirming the pharmacokinetics of CxP-AM. The decay rate of CxP-AM determined with time-resolved ESR-CT imaging was different in the two brain regions, suggesting regional differences in the total reducing capability. CxP-AM should become a powerful probe for the investigation and diagnosis of free radical reactions and their imaging in the brain.
Sano
H
H
Department of Biophysics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Naruse
M
M
Matsumoto
K
K
Oi
T
T
Utsumi
H
H
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D001927:Brain Diseases / Q000175:diagnosis*; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011759:Pyrrolidines / Q000138:chemical synthesis*; D013113:Spin Labels / Q000138:chemical synthesis*
D003497:Cyclic N-Oxides; D005609:Free Radicals; D011759:Pyrrolidines; D013113:Spin Labels; C411446:acetoxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylate; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase