Synthesis, characterisation and evaluation of a novel copper-64 complex with selective uptake in EMT-6 cells under hypoxic conditions.

Academic Article

Abstract

  • The radiometal (64)Cu is now widely used in the development of diagnostic imaging agents for positron emission tomography (PET). The present study has led to the development and evaluation of a novel chelating agent for (64)Cu: the new monothiourea tripodal ligand 1-benzoyl-3-{6-[(bis-pyridin-2-ylmethyl-amino)-methyl]-pyridin-2-yl}-thiourea (MTUBo). X-ray crystallographic analysis has shown this ligand forms a mononuclear complex with copper(II) and co-ordinates via a trigonal bipyramidal N4S array of donor atoms. Promisingly, cell uptake studies revealed that (64)Cu-MTUBo selectively accumulates in EMT-6 cells incubated under hypoxic conditions which may result from its relatively high Cu(II/I) redox potential. Small-animal PET imaging and ex vivo biodistribution studies in EMT-6 tumor bearing BALB/c mice revealed significant tumor uptake after 1 h p.i., yielding tumor-to-muscle (T/M) and tumor-to-blood (T/B) ratios of 8.1 and 1.1, respectively. However, injection of (64)Cu-acetate resulted in similar uptake indicating that the observed uptake was most likely non-specific. Despite showing high in vitro stability, it is likely that in vivo the complex undergoes transchelation to proteins within the blood in a relatively short timeframe. For comparison, the hypoxia imaging agent (64)Cu-ATSM was also evaluated in the same murine tumor model and showed about 60% higher tumor uptake than (64)Cu-MTUBo.
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    Keywords

  • Animals, Cell Hypoxia, Copper Radioisotopes, Crystallography, X-Ray, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Structure, Organometallic Compounds, Positron-Emission Tomography, Sarcoma, Experimental, Tissue Distribution
  • Digital Object Identifier (doi)

    Author List

  • Knight JC; Wuest M; Saad FA; Wang M; Chapman DW; Jans H-S; Lapi SE; Kariuki BM; Amoroso AJ; Wuest F
  • Start Page

  • 12005
  • End Page

  • 12014
  • Volume

  • 42
  • Issue

  • 33