Rhenium Analogues of Promising Renal Imaging Agents with a {^99mTc(CO)₃}⁺ Core Bound to Cysteine-Derived Dipeptides, Including Lanthionine

Abstract

The coordination chemistry of lanthionine (LANH2) and cystathionine (CSTH2) dipeptides, which respectively consist of two cysteines and one cysteine and one homocysteine linked by a thioether bridge, is almost unstudied. Recently for fac-[99mTc(CO)3(LAN)]- isomers, the first small 99mTc(CO)3 agents evaluated in humans were found to give excellent renal images and to have a high specificity for renal excretion. Herein we report the synthesis and characterization of Re complexes useful for interpreting the nature of tracer 99mTc radiopharmaceuticals. Treatment of [Re(CO)3(H2O)3]OTf with commercially available LANH2 (a mixture of meso (d,l) and chiral (dd,ll) isomers) gave three HPLC peaks, 1A, 1B, and 1C, but treatment with CSTH2 (l,l isomer) gave one major product, Re(CO)3(CSTH) (2). Crystalline Re(CO)3(LANH) products were best obtained with synthetic LANH2, richer in meso or chiral isomers. X-ray crystallography showed that these dipeptides coordinate as tridentate N2S-bound ligands with two dangling carboxyls. The LANH ligand is meso in 1A and 1C and chiral in 1B. While 1A (kinetically favored) is stable at ambient temperature for days, it converted into 1C (thermodynamically favored) at 100 degrees C; after 6 h, equilibrium was reached at a 1A:1C ratio of 1:2 at pH 8. The structures provide a rationale for this behavior and for the fact that 1A and 1C have simple NMR spectra. This simplicity results from fluxional interchange between an enantiomer with both chelate rings having the same delta pucker and an enantiomer with both chelate rings having the same lambda pucker. Agents with the [99mTc(CO)3]+ core and N2S ligands show promise of becoming an important class of 99mTc radiopharmaceuticals. The chemistry of Re analogues with these ligands, such as the LAN2- complexes reported here, provides a useful background for designing new small agents and also tagged large agents because two uncoordinated carboxyl groups are available for conjugation with biological molecules such as proteins.

Coordination Modes of Multidentate Ligands infac-[Re(CO)3(polyaminocarboxylate)] Analogues of99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

“…In our previous studies of fac -[Re(CO) 3 L] n analogues of 99m Tc renal agents with dangling carboxyl groups, we found unusual shift dispersion of NH 1 H NMR signals in several solvents, including D 2 O and DMSO- d 6 (where L = S -methyl-L-cysteine,4 methionine,4 lanthionine,6 or ethylenediamine- N,N’ -diacetic acid3). Although much more study is needed, some guidelines are developing.…”

New Monodentate Amidine Superbasic Ligands with a Single Configuration infac-[Re(CO)3(5,5′- or 6,6′-Me2bipyridine)(amidine)]BF4Complexes

“…Thus, the investigation of fac -[Re I (CO) 3 L] n complexes both aids in interpreting the chemistry of the radiopharmaceuticals and offers the potential for the discovery of new chemistry, some of which could be applied to radiopharmaceutical development. 18–19 …”

NH NMR Shifts of New Structurally Characterized fac-[Re(CO)3(polyamine)]n+ Complexes Probed via Outer-Sphere Hydrogen-Bonding Interactions to Anions, Including the Paramagnetic [ReIVBr6]2− Anion

“…For example, dangling uncoordinated carboxyl groups (which are negatively charged and deprotonated at physiological pH) usually become neutral protonated groups in procedures employed to crystallize the complex 1,2,20-22. One goal of our study is to interpret how NMR spectra inform us about the solution structure of fac -[Re(CO) 3 L] n complexes.…”