TY - JOUR
T1 - Technetium Nitrido Complexes of Tetradentate Thiosemicarbazones
T2 - Kit-Based Radiolabeling, Characterization, and In Vivo Evaluation
AU - Kelderman, Cormac A.A.
AU - Maclean, Rachel C.
AU - Hungnes, Ingebjørg N.
AU - Davey, Patrick R.W.J.
AU - Salimova, Ekaterina
AU - de Veer, Michael
AU - Patel, Natasha
AU - Ma, Michelle T.
AU - Paterson, Brett M.
N1 - Funding Information:
The authors acknowledge the Australian Research Council (DE170100540) and the School of Chemistry, Monash University for funding, the National Imaging Facility for a fellowship (B.M.P.), and the Australian Government for supporting this research with a Research Training Program Scholarship (C.A.A.K., R.C.M., and P.R.W.J.D.). This publication was also supported by a Monash University Faculty of Science Postgraduate Publication Award (C.A.A.K.). The authors acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at Monash Biomedical Imaging, Monash University and the Centre for Advanced Imaging, The University of Queensland. We thank the personnel at the Monash Analytical Platform, School of Chemistry, Monash University. We thank Dr. Charlotte Rivas and Dr. Thomas R Eykyn for experimental assistance. This research was supported in part by the Monash eResearch Centre and eSolutions-Research Support Services through use of the MonARCH HPC Cluster and the Digital Research Alliance of Canada. We also thank Professor S. R. Batten and Emeritus Professor K. S. Murray (School of Chemistry, Monash University) for the use of their laboratory facilities and Professor Paul Donnelly for valuable discussions.
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/12/18
Y1 - 2023/12/18
N2 - Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the 64Cu2+ complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with 99mTc, the most widely used radionuclide in nuclear medicine, is underexplored. Herein, a series of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators were radiolabeled with nitrido-technetium-99m in an optimized one-pot synthesis from [99mTc]TcO4-. Optimization of the radiochemical syntheses allowed for production of the complexes in >90% radiochemical conversion with apparent molar activities of 3.3-5 GBq/μmol. Competition experiments demonstrated the excellent stability of the complexes. The nitrido-technetium-99 complexes were synthesized, and the chemical identities were investigated using mass spectrometry, spectroscopy, and density functional theory calculations. Complexation of nitrido-rhenium(V) was achieved with the N4-dialkylated bis(thiosemicarbazones). Planar imaging and ex vivo biodistribution studies of the five 99mTc complexes were conducted on healthy BALB/c mice to determine in vivo behavior. The lipophilic nature of the complexes resulted in uptake of 1.6-5.7% ID g-1 in the brain at 2 min postinjection and retention of 0.4-1.7% ID g-1 at 15 min postinjection. The stability of the complexes and the biodistribution data demonstrate that these chelators are ideal platforms for future production of radiopharmaceutical candidates.
AB - Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the 64Cu2+ complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with 99mTc, the most widely used radionuclide in nuclear medicine, is underexplored. Herein, a series of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators were radiolabeled with nitrido-technetium-99m in an optimized one-pot synthesis from [99mTc]TcO4-. Optimization of the radiochemical syntheses allowed for production of the complexes in >90% radiochemical conversion with apparent molar activities of 3.3-5 GBq/μmol. Competition experiments demonstrated the excellent stability of the complexes. The nitrido-technetium-99 complexes were synthesized, and the chemical identities were investigated using mass spectrometry, spectroscopy, and density functional theory calculations. Complexation of nitrido-rhenium(V) was achieved with the N4-dialkylated bis(thiosemicarbazones). Planar imaging and ex vivo biodistribution studies of the five 99mTc complexes were conducted on healthy BALB/c mice to determine in vivo behavior. The lipophilic nature of the complexes resulted in uptake of 1.6-5.7% ID g-1 in the brain at 2 min postinjection and retention of 0.4-1.7% ID g-1 at 15 min postinjection. The stability of the complexes and the biodistribution data demonstrate that these chelators are ideal platforms for future production of radiopharmaceutical candidates.
UR - http://www.scopus.com/inward/record.url?scp=85176964310&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.3c02650
DO - 10.1021/acs.inorgchem.3c02650
M3 - Article
C2 - 37855107
AN - SCOPUS:85176964310
SN - 0020-1669
VL - 62
SP - 20791
EP - 20805
JO - INORGANIC CHEMISTRY
JF - INORGANIC CHEMISTRY
IS - 50
ER -