NW/. led. Biol. Vol. 20, No. 7. pp. 857-863, 1993 Printed in Great Britain. All rights reserved 0969-8051/93 S6.00 + 0.00 Copyright Q 1993 Pergamon Press Ltd Potential 99mT~Radiopharmaceuticals for Renal Imaging: Tris(N-substituted-3-hydroxy-2-methyl-d- pyridinonato)technetium(IV) Cations D. SCOTT EDWARDS’, SHUANG LIU’, DONALD M. LYSTER3, MICHAEL J. POIRIER’, CAN V03, GORDON A. WEBB2, ZAIHUI ZHANGZ and CHRIS 0RVIG2* ‘The Du Pont Merck Pharmaceutical Company, Radiopharmaceutical Division, 331 Treble Cove Road. N. Billerica, MA01862, U.S.A., 2Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Zl and )Division of Nuclear Medicine, Vancouver General Hospital. Vancouver, British Columbia, Canada V5Z lM9 zyxwvutsrqponmlkjihgfedcbaZY (Received 25 March 1993) A series of monocationic complexes of N-substituted-3-hydroxy-2-methyl-4-pyridinones labeled with technetium(IV)-99m have been evaluated in vivo as potential radiopharmaceuticals. The pyridinones have different substituents at the ring nitrogen atom: ethyl, i-propyl, i-butyl, benzyl, phenyl, p-methoxyphenyl. 3-butoxypropyl and cyclohexyl. Biodistribution studies of the WmTc complexes have been carried out in rabbits and mice. High kidney uptake and retention of the radionuclide has been shown in rabbits and mice with the cationic complexes of 3-hydroxy-l-(p-methoxyphenyl)-2-methyl-4-pyridinone and I-(cyclo- hexyl)-3-hydroxy-2-methyl-4-pyridinone. These %TcL: compounds appear to be morphologic renal Introduction Recent focus in technetium chemistry has been on the design and preparation of new technetium complexes, the lipophilicity, polarity and overall charge of which can be readily altered by simple substitutions in the molecular framework of the ligand in order to optimize the biodistribution and target specific organs. Examples are cationic (Cardio- lite@) and neutral (Ceretec@) technetium complexes, used as myocardial and brain imaging agents, respectively. We have reported tris(3-hydroxy-4-pyridinone)- gallium and -indium complexes that are water soluble, hydrolytically stable and of varying lipophilicity and neutral charge (Matsuba et al., 1988; Nelson et al., 1988, 1989; Clevette ef al., 1990; Clevette and Orvig, 1990; Zhang ef al., 1991). This combination of properties, and the great mobility of these complexes in uiuo, has suggested their potential application as heart imaging agents (Zhang et al., 1992). In an effort to extend these properties to technetium, we have investigated the chemistry of technetium complexes with these same Iigands (Scheme 1). In work to be published separately, using *Author for correspondence. Y4mT~ and 9qc we have discovered these compounds to be tris(ligand)technetium(IV) cations TcL;. In this report, we present the results of in &I studies obtained with tris(N-substituted-3-hydroxy- 4-pyridinonato)technetium-99m cationic complexes in rabbits and mice, and we comment on the potential application of these complexes as nuclear imaging agents. Experimental The ligands I-ethyl-3-hydroxy-2-methyl-4-pyri- dinone (Hmepp), 3-hydroxy-2-methyl-l-(phenyl)-l- pyridinone (Hppp) and 3-hydroxy-l-(p-methoxy- phenyl)-2-methyl-4-pyridinone (Hpap) were syn- thesized as described previously (Nelson et al., 1989; Zhang et al., 1991). Malt01 (3-hydroxy-2-methyl- 4-pyrone), isopropylamine, isobutylamine, benzyl- amine, cyclohexylamine, 3-butoxypropylamine and sodium bisulfite were purchased from Aldrich Chemi- cal Co., Milwaukee, Wis., and were used as received. Na99mTc0, was obtained from a Du Pont 99Mo/99mT~ generator. Deionized water was obtained from a Millipore MilliQ Water System and was of > 18 Mfi quality. All other chemicals and solvents were obtained from commercial sources and were used as received. 857