ChemInform Abstract: Novel Nitroxides for Spin-Labelling, -Trapping, and Magnetic Resonance Imaging Applications

Abstract

We describe the synthesis of the isotopically labelled nitrone spin traps 7,9, and 10, and spin labelled cytochalasin B derivatives 15 23. We describe a new general route to proxy1 nitroxide spin labelled fatty acids, for example, 28 and 29, and the 15Nnonadeutero 1 1-proxylpalmitic acid P-OH. New types of paramagnetic liposomes derived from bis nitroxide quaternary salts 31 and 32 have been prepared. Molecules designed as molecular amplifiers such as hexaamine 35a are described. Paramagnetic centers such as a nitroxide epoxide or Gd complex 37 may be attached giving unique spin relaxers such as 35b and 35c to which an isothiocyanate reactive group may be added giving 36b and 36c. INTRODUCTION Stable nitroxide free radicals continue to play a central role in a wide variety of investigations, especially involving spin labelling and spin trapping applications. More recently, novel applications have arisen in which nitroxides are being developed as contrast-enhancing agents for magnetic resonance imaging (MRI) and as paramagnetic agents for the relatively new field of imaging by electron spin resonance (ESR) spectroscopy. In this paper we summarize several recent developments in our laboratory in the nitroxide field. I. Development of *Hand '5N-isotopically substituted nitrone spin traps organic free radicals. In this method an appropriate nitrone or nitroso compound reacts with the short lived radical intermediate producing a nitroxide with a lifetime considerably greater than that of the parent radical. Recent advances in spin trapping include the preparation of a family of pyrrolidine-I-oxide spin traps with enhanced lipophilicity and a decreased tendency toward oxidation3 and the preparation of nitrones which react preferentially with hydroxyl radical over superoxide.4 Spin trapping12 has proven to be a powerful tool for the identification of biologically generated transient One difficulty encountered in the spin trapping of certain free radical intermediates, for example superoxide, is the rather slow rate (-10 M-hec-1) with which nitrones react with the intermediate. Thus potentially toxic concentrations of the nitrone are required for efficient trapping in biological systems. Our aim in this section is to develop nitrone-based spin traps with improved sensitivity owing to isotopic substitution. Our approach is based on the pioneering work of Beth et al.5 and Janzen et a1.6 These groups showed that a significant increase in ESR sensitivity could be achieved by preparing nitroxides that contain 2H and 15N in place of IH and 14N, respectively. Herein we report the synthesis of a family of such isotopically substituted nitrones and a study of their ability to spin trap superoxide and hydroxyl radicals generated from a model superoxide-generating system. 00GcX; C I I RyJ RQ; /O' 4, X, Y = / O H 1, X,Y=15N D 7, R=C&;N=% 8, R = CH3; N 14N 9, R = CD3; N = 15N 10, R = CH3; N = 14N