Re(CO)3 Complexes Synthesized via an Improved Preparation of Aqueous fac-[Re(CO)3(H2O)3]+ as an Aid in Assessing 99mTc Imaging Agents. Structural Characterization and Solution Behavior of Complexes with Thioether-Bearing Amino Acids as Tridentate Ligands

Abstract
Parallel studies of the preparation of Re and 99mTc agents aid in interpreting the nature of tracer 99mTc radiopharmaceuticals. Aqueous solutions of the fac-[99mTc(CO)3(H2O)3]+ cation are gaining wide use and are readily prepared, but such solutions of the fac-[Re(CO)3(H2O)3]+ cation (1) are not so easily accessible. Herein we describe a new, reliable, and straightforward preparation of aqueous solutions of 1, characterized by HPLC and ESI-MS. Treatment of solutions of 1 with thioether-bearing amino acids, AAH = S-methyl-l-cysteine (MECYSH), S-propyl-l-cysteine (PRCYSH), and methionine (METH), gave high yields of fac-Re(CO)3AA complexes. X-ray crystallographic and NMR analyses indicated that MECYS-, PRCYS-, and MET- were bound in fac-Re(CO)3AA complexes as tridentate monoanionic ligands through amino, thioether, and α-carboxyl groups. In CD3OD, 1H NMR spectra have broad signals but have two sets of signals at −10 °C, consistent with two isomers with different configurations at the pyramidal sulfur; these interconvert slowly on the NMR time scale at low temperatures. Indeed, the crystal structure of the fac-Re(CO)3(PRCYS) reveals a mixture of the two possible diastereoisomers. S-(Carboxymethyl)-l-cysteine (CCMH2) and 1 gave two products, 5A (kinetically favored) and 5B (thermodynamically favored). X-ray crystallographic analyses of a crystal of 5B and of a 1:1 cocrystal of 5A and 5B showed that 5A and 5B are diastereoisomers with the CCMH- α-carboxyl group dangling. In addition to the amino and thioether groups, the S-(carboxymethyl) carboxyl group is coordinated, a feature that slows interconversion of diastereoisomers relative to the other fac-Re(CO)3AA complexes because interconversion can now occur only after the rupture of Re−ligand bonds. These N, O, and S tridentate adducts are quite stable, and the grouping has promise in 99mTc(CO)3 tracer development.

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