Rhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-β plaques

Abstract

Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99 m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]3+ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-β targeting functional groups. The interaction of the [Re-oxo]3+ complexes with synthetic amyloid-β1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [99mTc-oxo]3+ complexes at the tracer level. These technetium-99 m complexes are likely to be isostructural to their rhenium-oxo analogues.

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Acknowledgements

The Australian Research Council (Grant Nos. DP160100288, FT130100204) for funding this research. The Victorian Brain Bank for provision of human brain tissue. We acknowledge the generous support of Prof. Andrew M. Scott, A/Prof. Henri Tochon-Danguy, A/Prof. Uwe Ackermann, Dr. FT Lee, Nick Alexopoulos, and David Thomas of the Austin Hospital, Heidelberg, Victoria, Australia, for providing access to 99mTc and radiochemistry facilities. Associate Professors Kevin Barnham and Victor Villemagne are acknowledged for their ongoing advice and guidance in this area of research.

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Correspondence to Paul S. Donnelly.

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Fletcher, S.P., Noor, A., Hickey, J.L. et al. Rhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-β plaques. J Biol Inorg Chem 23, 1139–1151 (2018). https://doi.org/10.1007/s00775-018-1590-4

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Keywords

  • Technetium
  • Rhenium
  • Amyloid-β
  • Imaging