Nitroxyl radicals for labeling of conventional therapeutics and noninvasive magnetic resonance imaging of their permeability for blood-brain barrier: relationship between structure, blood clearance, and MRI signal dynamic in the brain.
The present study describes a novel nonradioactive methodology for in vivo noninvasive, real-time imaging of blood-brain barrier (BBB) permeability for conventional drugs, using nitroxyl radicals as spin-labels and magnetic resonance imaging (MRI). Two TEMPO-labeled analogues (SLENU and SLCNUgly) of the anticancer drug lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] were synthesized, using a substitution of the cyclohexyl part with nitroxyl radical. Nonmodified nitroxyl radical TEMPOL was used for comparison. The nitroxyl derivatives were injected intravenously in healthy mice via the tail vein, and MR imaging of the brain was performed on a 7.0 T MRI. The MRI signal dynamic of SLENU and SLCNUgly followed the same kinetics as nonmodified TEMPO radical. SLENU and SLCNUgly were rapidly transported and randomly distributed in the brain tissue, which indicated that the exchange of cyclohexyl part of lomustine with TEMPO radical did not suppress the permeability of the anticancer drug for BBB. The selected nitroxyl derivatives possessed different hydrophobicity, cell permeabilization ability, and blood clearance. Based on these differences, we investigated the relationship betweenthe structure of nitroxyl derivatives, their half-life in the circulation, and their MRI signal dynamic in the brain. This information was important for estimation of the merits and demerits of the described methodology and finding pathways for overcoming the restrictions.
Zhelev
Zhivko
Z
Department of Biophysics, Molecular Imaging Center, and Center for Heavy-ion Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Bakalova
Rumiana
R
Aoki
Ichio
I
Matsumoto
Ken-ichiro
K
Gadjeva
Veselina
V
Anzai
Kazunori
K
Kanno
Iwao
I
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D001783:Blood Flow Velocity; D001812:Blood-Brain Barrier / Q000033:anatomy & histology* / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D008130:Lomustine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009589:Nitrogen Oxides / Q000737:chemistry*; D013113:Spin Labels; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D013113:Spin Labels; D008130:Lomustine; C039900:nitroxyl; C001803:tempol