Re(V)=O(N2S2) complexes with N2S2 = thio-amido-secondary amine-thio chelate ligands: Synthesis, structure, and characterization of solution forms

Anti- and syn-ReO(L-cysteine-acetyl-cysteamine) (1 and 2, respectively), an d the dimethyl derivatives anti- and syn-ReO(L-penicillamine-acetyl-cysteam ine) (3 and 4, respectively), were synthesized. Anti and syn refer to the r elationship of the oxo ligand and carboxyl group of the cysteine/penicillam ine 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 investig ated 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 essent ial 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 H-1 NMR spectra, monitored as a function of pH, exhibited changes in two pH re gions: near pH 4 the signals (especially the H-alpha of the cysteine residu e) shifted, and from pH similar to 6-8 the signals shifted again and broade ned. These shift changes are consistent with dissociation of the carboxyl p roton to give a monoanion I, and of the amine proton to give a dianion II, respectively. The cysteamine chelate ring of I and 4, anchored by the amine -donor, is highly puckered in the solid stare. Torsion angles, calculated f rom H-1 NMR (3)J values at pH 3, 5 and 8, indicate that in solution the cys teamine 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 b eing an NH-deprotonated form rather than an OH- axially ligated form. The h igh acidity of the amine in 1 and 2 compared to analogues with two amine do nors indicates that the amido group is a modest donor. The signal broadenin g 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 neede d Co convert I to II. Making the metal (Re/Tc) more electron rich may decre ase the acidity of the NH, bur since the NH in 1 and 2 is particularly acid ic, this approach is unlikely to work. Our results suggest that introductio n of an electron-withdrawing group into the ligand may lower the NH pK(a) o f the complex below the physiologically relevant range and give a species w ith a well-defined charge.