Development of nonreducible technetium-99m(III) cations as myocardial perfusion imaging agents: initial experience in humans

A series of 15 nonreducible technetium-99m(III) complexes of formula tr-[99mTcL(Y)2]+ has been prepared by a general synthetic route based on reductive addition of Y to the technetium-99m (99mTc) intermediate [99mTcL(O)]+. In these complexes, selected for potential use as myocardial imaging agents, L represents one of the two tetradentate Schiff base ligands N,N'-ethylenebis(acetylacetone iminato), (en), or N,N'-propylene-1,2-bis(acetylacetone iminato), (pn), while Y represents a monodentate phosphine, phosphite or isonitrile ligand as exemplified by P(CH3)3, P(OCH3)3 and CN-C(CH3)3. Of these 15 complexes, several with octanol/saline partition coefficients in the range 0.04-20 exhibit significant myocardial uptake in rats and dogs. Of these, none exhibit detectable myocardial washout, providing strong support for the hypothesis that myocardial washout occurs only for those 99mTc(III) cations that undergo in vivo reduction to the neutral 99mTc(II) form. Evaluation of the prototypical complex tr-[99mTc(en)(P(CH3)3)2]+ in seven normal volunteers and patients establishes that it is only a mediocre myocardial imaging agent in man.