Zirconium Coordination Chemistry and Its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics

In the past decade, there has been a growth in using Zirconium-89 (89Zr) as a radionuclide in nuclear medicine for cancer diagnostic imaging and drug discovery processes. Although one of the most popular chelators for 89Zr, desferrioxamine (DFO) is typically presented as a hexadentate ligand, our work suggests a different scenario. The coordination structure of the Zr4+–DFO complex has primarily been informed by DFT-based calculations, which typically ignore temperature and therefore entropic and dynamic solvent effects. In this work, free energy calculations using molecular dynamics simulations, where the conformational fluctuations of both the ligand and the solvent are explicitly included, are used to compare the binding of Zr4+ cations with two different chelators, DFO and 4HMS, the latter of which is an octadentate ligand that has been recently proposed as a better chelator due to the presence of four hydroxymate groups. We find that thermally induced disorder leads to an open hexadentate chelate structure of the Zr4+–DFO complex, leaving the Zr4+ metal exposed to the solvent. A stable coordination of Zr4+ with 4HMS, however, is formed by involving both hydroxamate groups and water molecules in a more closely packed structure

Zirconium Coordination Chemistry and its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics

In the last decade, there has been a growth in using Zirconium-89 (89 Zr) as a radionuclide in nuclear medicine for cancer diagnostic imaging and drug discovery processes. One of the most popular chelators for 89 Zr, is desferrioxamine (DFO) which acts as a hexadentate ligand. The coordination structure of the Zr4+-DFO complex has primarily been informed by DFT-based calculations which typically ignore temperature and therefore entropic and dynamic solvent effects. In this work, free energy calculations using molecular dynamics simulations, where the conformational fluctuations of both the ligand and the solvent are explicitly included, are used to compare the binding of Zr4+ cation with two different chelators, DFO and 4HMS, the latter of which has been recently proposed as a better chelator. We find that thermal induced disorder leads an open hexadentate chelate structure of Zr4+-DFO complex, leaving the Zr4+ metal exposed to the solvent. A stable coordination of Zr4+ with 4HMS, however, is formed involving both hydroxamate groups and water molecules in a more closely packed structure

Clinical utility of indigenously formulated single-vial lyophilized HYNIC-TOC kit in evaluating Gastro-entero Pancreatic neuro endocrine tumours

  Objective(s): The objective of this study was to evaluate the performance and utility of 99mTc HYNIC-TOC planar scintigraphy and SPECT/CT in the diagnosis, staging and management of gastroenteropancreatic neuroendocrine tumors (GPNETs). Methods: 22 patients (median age, 46 years) with histologically proven gastroentero-pancreatic NETs underwent 99mTc HYNIC-TOC whole body scintigraphy and regional SPECT/CT as indicated. Scanning was performed after injection of 370-550 MBq (10-15 mCi) of 99mTc HYNIC-TOC intravenously. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as semi quantitatively (tumor to background and tumor to normal liver ratios on SPECT -CT images). Results of SPECT/CT were compared with the results of conventional imaging. Histopathology results and follow-up somatostatin receptor scintigraphy with 99mTc HYNIC TOC or conventional imaging with biochemical markers were considered to be the reference standards. Results: 99mTc HYNIC TOC showed sensitivity and specificity of 87.5% and 85.7%, respectively, for primary tumor and 100% and 86% for metastases. It was better than conventional imaging modalities for the detection of both primary tumor (