DESIGN OF HYPOXIA-TARGETING RADIOPHARMACEUTICALS - SELECTIVE UPTAKE OF COPPER-64 COMPLEXES IN HYPOXIC CELLS IN-VITRO

The well-known perfusion tracer CuPTSM, labelled with Cu-62 or Cu-64 i s believed to be trapped in cells non-selectively by a bioreductive me chanism. It is proposed that by modifying the ligand to increase its e lectron donor strength (for example by adding alkyl functionality or r eplacing sulphur ligands with oxygen ligands), the copper complexes wi ll become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare Cu-64-labelled complexes of two series of ligands, based on the bis(th iosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) ske letons, and to evaluate the hypoxia dependence of their uptake in cell s. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifuga tion to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P<0.05) or highly significant (P<0.01) hypoxia selectivity, indicating that b oth series of complexes offer a basis for development of hypoxia-targe ting radiopharmaceuticals for positron emission tomography (Cu-60, Cu- 61, Cu-62, Cu-64) and targeted radiotherapy (Cu-64, Cu-67).