Factors influencing the pK(a) of ligated amines and the syn/anti isomerization in cysteine-based Re(V)=O(N2S2) radiopharmaceutical analogues as revealed by a novel dominant tautomer in the solid state

Efficient radiopharmaceutical design demands an understanding of factors th at lead to one isomeric species in one ionization state at physiological pH . Thus, all pK(a) values must be outside the range of 6-9 for the typical M (V)O(N2S2) (M = Tc-99m, Re-186/188) agents. The pendant carboxyl group need ed for rapid clearance of renal agents in particular must be either only sy n or only anti to the oxo ligand with respect to the N2S2 ligand plane. Mon oamide-monoamine-dithiol (monoamide-monoamine = MAMA) ligands useful in pre paring radiopharmaceuticals typically form M(V)O(N2S2) complexes with one c ore ligand pK(a) of similar to 6-7 (secondary amine) and with both syn and anti isomers. We designed a new MAMA ligand, mercaptoacetamide-ethylene-cys teine (MAECH(5)), with the electron-withdrawing carboxyl group separated by only two bonds from the NH group. Only syn-ReO(MAECH(2)) was isolated. The structure of the monoanion syn-[ReO(MAECH)](-) in the crystal of a [AsPh4] (+) salt reveals lattice H-bonding between the CO2H of a tautomer (t(2)) wi th a CO2H and an amine N- and the C=O of a neighboring t(2) anion; this int eraction results in preferential crystallization of t(2). However, in aqueo us solutions of syn-[ReO(MAECH)](-), the predominant monoanionic tautomer ( t(1)) has a CO2- and an amine NH, as indicated by H-1 NMR and resonance Ram an spectra, The endo-NH configuration favored in M(V)O(N2S2) complexes plac es the NH and CO2- groups in t(1) spatially close. The NH is less acidic du e to the cancellation of the electron-withdrawing and electrostatic effects of the negative CO2-; as a result, syn-[ReO(MAECH)](-) has a pK(a) value ( 6.0 +/- 0.1) similar to that of the regioisomer syn-[ReO(CACAH)](-) in whic h the carboxyl group and the NH are not close (CACAH(5) = cysteine-acetyl-c ysteamine). Our results suggest that the carboxyl group position also influ ences the syn/anti equilibrium. Attachment of the carboxyl group to a pucke red ring in syn-[ReO(MAECH)](-) appears both to favor the syn isomer and to increase the rate of syn/anti isomerization. ReO(CACAH(2)), with a carboxy l group attached to a less puckered chelate ring anchored by the amido dono r, formed as a noninterconverting roughly equal mixture of syn/anti isomers . Thus, for a MAMA ligand to form a syn isomer with a pK(a) < 6, it must be designed with a nonionizable electron-withdrawing group near the NH group and a pendant carboxyl on a puckered ring.