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-PROXL acetoxymethyl ester (C xP-AM) was newly synthesized. CxP-AM was designed to be hydrolyzed by ester ase, but not by lipase, so that it would pass through the blood-brain barri er and be retained in the cytosolic phase of parenchymal cells in the brain after intravenous injection. The pharmacokinetics of CxP-AM was compared w ith those of carboxy-PROXYL (CxP) and its methyl ester (CxP-M). Carboxyl es terase almost completely hydrolyzed CxP-AM within 3 min. After intravenous injection, the brain retained 1.8 times more CxP-AM than CxP-M, and retaine d it for more than 30 min. Electron spin resonance computed tomographic (ES R-CT) imaging of CxP-AM in the heads of mice produced marked contrast in th e encephalon region, while CxP was distributed only in the extracranial reg ion and CxP-M was distributed in both regions, confirming the pharmacokinet ics of CxP-AM. The decay rate of CxP-AM determined with time-resolved ESR-C T imaging was different in the two brain regions, suggesting regional diffe rences in the total reducing capability. CxP-AM should become a powerful pr obe for the investigation and diagnosis of free radical reactions and their imaging in the brain. (C) 2000 Elsevier Science Inc.