Structural elucidation and dynamic studies of MO tripeptide diastereomers (M = technetium-99m, technetium-99, rhenium): An extension to targeted radiopharmaceuticals.

摘要

Neotect(TM) (99mTc depreotide), the first targeted radiopharmaceutical that entered clinical use as imaging agent for lung tumors, consisted of two species that were purportedly identified as syn and anti diastereomers based on NMR, mass spec, and IR data. Because their biological behaviors are significantly different, it was critical to obtain the absolute identity for each diastereomer. This dissertation has accomplished this goal using [MV=O] tripeptide diastereomers. Moreover, since the identification of these diastereomers is general for all 99mTc tripeptide (comprised of L amino acids) complexes, this information will aid in the identification of the 99mTc and 188Re radiopharmaceuticals when the [M=O]+3 core in a tripeptide binding site is employed.; We isolated 99Tc and Re diastereomers of several tripeptide ligands, including three (MKC, FKC, and YKC) that closely model 99m Tc depreotide. Using X-ray crystallography, we show that, as expected, the TcO is bound to the ligand in a square pyramidal coordination environment. The crystallography demonstrated that the early eluting peak (A) corresponds to the "anti" diastereomer where the Tc=O group is on the opposite side of the square plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the "syn" diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. Moreover, 1H NMR and circular dichroism spectroscopy confirm that the 99/99mTc tripeptide models have the same diastereomer profile as 99/99mTc depreotide.; Observations made during the syntheses of 99Tc and Re diastereomers provided hypotheses for the stability of diastereomers. Stability of diastereomers was addressed by quantitative kinetic studies of the interconversion of the 99mTc analogs. We postulate that hydrogen bonding of residues, for example the epsilonNH3 of lysine with the -yl oxygen of the Tc/Re=O or with a carbonyl of the tripeptide in syn complexes, may be a stabilizing force. Also, the potential hydrogen bonding of the Tc=O with the C-terminal amide appears to be a stabilizing factor in MO FGC anti (M=Tc,Re) according to experimental kinetic studies and preliminary DFT calculations.