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New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents.

ABSTRACT: Multiple possibilities for the coordination of fac-[Re(CO)3(H2O)3]+ to a protein have been determined and include binding to Asp, Glu, Arg and His amino-acid residues as well as to the C-terminal carboxylate in the vicinity of Leu and Pro. The large number of rhenium metal complex binding sites that have been identified on specific residues thereby allow increased target identification for the design of future radiopharmaceuticals. The core experimental concept involved the use of state-of-art tuneable synchrotron radiation at the Diamond Light Source to optimize the rhenium anomalous dispersion signal to a large value (f'' of 12.1 electrons) at its LI absorption edge with a selected X-ray wavelength of 0.9763?Å. At the Cu?K? X-ray wavelength (1.5418?Å) the f'' for rhenium is 5.9 electrons. The expected peak-height increase owing to the optimization of the Re f'' was therefore 2.1. This X-ray wavelength tuning methodology thereby showed the lower occupancy rhenium binding sites as well as the occupancies of the higher occupancy rhenium binding sites.

SUBMITTER: Brink A

PROVIDER: S-EPMC5414402 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents.

Brink Alice A Helliwell John R JR

IUCrJ 20170411 Pt 3

Multiple possibilities for the coordination of fac-[Re(CO)3(H2O)3]+ to a protein have been determined and include binding to Asp, Glu, Arg and His amino-acid residues as well as to the C-terminal carboxylate in the vicinity of Leu and Pro. The large number of rhenium metal complex binding sites that have been identified on specific residues thereby allow increased target identification for the design of future radiopharmaceuticals. The core expe ...[more]

PMID: 28512575

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Project description:A pentapeptide macrocyclic ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for SPECT imaging and therapeutic in vivo agents. This study shows the synthesis and characterization of KYCAR complexes containing nonradioactive rhenium, 99mTc, or 188Re. The metal complexes were also biologically evaluated to determine in vivo distribution in healthy mice. The overall goals of this project were (1) to synthesize the Tc/Re pentapeptide complexes, (2) to identify spectroscopic methods for characterization of syn versus anti rhenium peptide complexes, (3) to analyze the ex vivo stability, and (4) to assess the biological properties of the [99mTc]TcO-KYCAR and [188Re]ReO-KYCAR complexes in vivo. Details on these efforts are provided below.MethodsNatRe/99mTc/188ReO-KYCAR complexes were synthesized, and macroscopic species were characterized via HPLC, IR, NMR, and CD. These characterization data were compared to the crystallographic data of ReO-KYC to assist in the assignment of diastereomers and to aid in the determination of the structure of the complex.ResultsThe radiometal complexes were synthesized with high purity (>95%). HPLC, IR, NMR and CD data on the macroscopic natReO-KYCAR complexes confirm the successful complexation as well as the presence of two diastereomers in syn and anticonformations. Tracer level complexes show favorable stabilities ex vivo for 2+ h.ConclusionMacroscopic metal complexes form diastereomers with the KYCAR ligand; however, this phenomenon is not readily observed on the tracer level due to the rapid interconversion. It was determined through pKa measurements that the macroscopic natReO-KYCAR complex is 0 at physiological pH. The [99mTc]TcO-KYCAR is stable in vitro while the [188Re]ReO-KYCAR shows 50% decomposition in PBS and serum. Biologically, the tracer level complexes clear through the hepatobiliary pathway. Some decomposition of both tracers is evident by uptake in the thyroid and stomach.

Dataset Information

New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents.

Publications

New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents.

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