Synthesis, chelating properties towards gallium and biological evaluation of two N-substituted 3-hydroxy-4-pyridinones

Two N-substituted 3-hydroxy-4-pyridinones (1-(3'-aminopropyl)-3-hydroxy-2-m ethyl-4 (L1) and 1-(2'-carboxyethyl)-3-hydroxy-2-methyl-4-pyridinone (L-2)) were prepared through one- and three-step reactions, respectively. The pK( a) values of the ligands and the stability constants of their Ga(III) compl exes have been determined. Both the complexes are strongly coordinated to t hree {O,O} hydroxypyridonate moieties. There is a clear effect of the N-sub stituents in the lipophilic-hydrophilic balance and in the Ga(III) binding interaction; the acid derivative (L-2) has lower lipophilicity but higher c helating strength than the amine derivative (L'). Both chelators are shown to interfere in the typical biological behavior of Ga-67-citrate in mice: L -1 enhanced the urinary excretion leading to an increased Ga-67 removal fro m the soft tissue, while L2 induced a lower blood clearance with a pronounc ed bone uptake mainly at 48 h after injection, thus suggesting that the (67 )G-L-2 complex could have potential interest as a bone imaging agent. (C) 2 000 Elsevier Science Inc. All rights reserved.