A general synthetic approach for potent tridentate, bifunctional chelating agent (BFCA) for the [M(CO)(3)](+) fragment (M=Tc-99g, Tc-99m, and Re) has be en elaborated. The strategy allows the facile preparation of BFCA with a pendent amino or carboxylic acid functionality for coupling to peptides and proteins via formation of an amide bond. [(5-amino-pentyl)-pyridin-2-yl-methyl-amino]-acetic acid (APPA) and [pyridin-2-yl-methyl-amino]-diacetic acid (PADA) were synthesized according to this protocol. The BFCA were labeled with the [M(CO)(3)](+) fragment, which resulted in formation of uniform products with a ligand to metal ratio of 1:1. The complexes have been fully characterized by means of mass spectrometry, IR, and NMR (H-1, C-13, Tc-99) spectroscopy. Coordination of the tricarbonyl core with APPA and PADA was exclusively tridentate (via the acid function, the ternary amine, and the pyridine nitrogen). On the n.c.a. level the complexes were almost quantitatively formed (yield>90%) at ligand concentrations of 10+/-2 muM (PADA) or 50+/-4 muM (APPA) after 30 min at 70degreesC. Chromatographic behavior of the Tc-99m complexes is similar to that of the corresponding Tc-99/Re complexes suggesting the identical chemical structure. Pharmacokinetic experiments with the Tc-99m-APPA complex were performed in BALB/c mice and compared with previously published results of the Tc-99m-PADA complex. The Tc-99m-APPA complex revealed good clearance from the blood pool (0.29+/-0.03% ID after 24h p.i.) and a low uptake in the liver (2.41+/-0.14% ID/g), in the kidneys (2.81+/-0.12% ID/g) and other tissue and organs. (C) 2003 Elsevier Inc. All rights reserved.
