Acyl-protected hydroxylamines as spin label generators for EPR brain imaging.
In a search for novel electron paramagnetic resonance (EPR) brain imaging agents, we have designed and synthesized the acyl-protected hydroxylamines 1-acetoxy-4-methoxycarbonyl-2,2,6,6-tetramethylpiperidine (AMCPe), 1-acetoxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (AMCPy), and 1-acetoxy-3-(acetoxymethoxy)carbonyl-2,2,5,5-tetramethylpyrrolidine (DACPy), in which both the ring size and the number of ester functions were varied. In all of them, the nitroxide was first reduced and the resultant hydroxylamine was then protected with an acetyl group. These compounds are lipophilic, which is a major prerequisite for blood-brain barrier penetration. Once in the brain, esterases and oxidants quickly convert these derivatives into ionic, water-soluble radicals and thus EPR detectable species that then reside in the central nervous system for periods of time sufficient for detection and imaging. The biological relevancy of these new compounds in mice has been assessed, and their biodistribution patterns have been compared. The five-membered ring derivative AMCPy emerged as a potent EPR brain imaging agent while the other two derivatives, AMCPe and DACPy, were quite ineffective.
Yordanov
Alexander T
AT
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. yordanov@mail.nih.gov
Yamada
Ken-ichi
K
Krishna
Murali C
MC
Russo
Angelo
A
Yoo
John
J
English
Sean
S
Mitchell
James B
JB
Brechbiel
Martin W
MW
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013113:Spin Labels / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
C455822:1-acetoxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine; D000085:Acetates; D006898:Hydroxylamines; D011759:Pyrrolidines; D013113:Spin Labels