Developments in imaging hypoxia: new tracers and data modelling


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Rehan Ali, Rebekka Hueting, Martin Christlieb

University of Oxford, UK

Abstract

Proffered paper presentation

Background
Tumour hypoxia is a killer and the current imaging methods have not yet proved themselves. Cu[ATSM] has promise, but is insoluble and shows accumulation in normoxic tissues. Copper is an interesting element having a number of positron emitting isotopes with a variety of half-lives. The labelling chemistry is straight forward, fast and suited to non-expert hands.

Method
Compounds were radiolabelled by mixing the free ligand or zinc complex with 64Cu(OAc)2 and purified by Sep-Pak (C18) cartridge. Tracer performance was assessed in HeLa cells under 0%, 0.2% and 21% oxygen concentrations. The bio-distribution was assessed by PET scan of copper-64 labelled compounds in BD9 rats with P22 tumour. Compartmental modelling of in vitro data followed the principles of mass balance kinetics using coupled ordinary differential equations. The quality of simulation was assessed using RMS deviation.

Results
Compounds are synthesised in good yield; many were soluble in water. Radiolabelling was efficient at room temperature in water. The compounds were radiochemically pure by HPLC. Cell uptake experiments showed oxygen dependant uptake over 60 minutes. PET results showed tumour uptake and structure dependant biodistribution and excretion routes. Coupling experiments demonstrated that coupling to a peptide (bombesin) was possible. Compartment models were able to simulate cell uptake data.

Conclusion
We have synthesised and radio-labelled new tracers of tumour hypoxia. We have also shown that copper bis(thiosemicarbazones) may be attached to peptides and proteins to label biomolecules. Mathematical modelling is able to reproduce experimental data and may be helpful in quantifying PET data.