Re(V)=O(N(2)S(2)) Complexes with N(2)S(2) = Thio-Amido-Secondary Amine-Thio Chelate Ligands: Synthesis, Structure,...

Anti- and syn-ReO(L-cysteine-acetyl-cysteamine) (1 and 2, respectively), and the dimethyl derivatives anti- and syn-ReO(L-penicillamine-acetyl-cysteamine) (3 and 4, respectively), were synthesized. Anti and syn refer to the relationship of the oxo ligand and carboxyl group of the cysteine/penicillamine residue. In the structures of 1 and 4, determined by X-ray diffraction, the oxo/carboxyl relationship was anti in 1 and syn in 4. Such thio-amido-amine-thio (MAMA for monoamido monoamine) type complexes are being investigated as radiopharmaceuticals. The charge and the number of species present under physiological conditions influence biodistribution, and understanding factors influencing the pK(a) of the coordinated secondary amine is essential for successful design of such agents. Dissociation of the proton on the secondary amine alters the charge and structure. For both 1 and 2, the (1)H NMR spectra, monitored as a function of pH, exhibited changes in two pH regions: near pH 4 the signals (especially the H(alpha) of the cysteine residue) shifted, and from pH approximately 6-8 the signals shifted again and broadened. These shift changes are consistent with dissociation of the carboxyl proton to give a monoanion I, and of the amine proton to give a dianion II, respectively. The cysteamine chelate ring of 1 and 4, anchored by the amine donor, is highly puckered in the solid state. Torsion angles, calculated from (1)H NMR (3)J values at pH 3, 5 and 8, indicate that in solution the cysteamine chelate ring is also highly puckered in the neutral form and I, but relatively planar in II. Since five-membered chelate rings are more planar when an anchoring amine is deprotonated, the data are consistent with II being an NH-deprotonated form rather than an OH(-) axially ligated form. The high acidity of the amine in 1 and 2 compared to analogues with two amine donors indicates that the amido group is a modest donor. The signal broadening observed as I and II interconvert, an unusual effect for NH/N(-) exchange, is due primarily to the low rate of exchange at the OH(-) concentration needed to convert I to II. Making the metal (Re/Tc) more electron rich may decrease the acidity of the NH, but since the NH in 1 and 2 is particularly acidic, this approach is unlikely to work. Our results suggest that introduction of an electron-withdrawing group into the ligand may lower the NH pK(a) of the complex below the physiologically relevant range and give a species with a well-defined charge.