Developing new PET tracers and studying them with new techniques
Martin Christlieb, Robert King
University of Oxford, Oxford, UK
Background
We are developing new analogues of Cu[ATSM], a PET tracer for hypoxia which has reached clinical trials in UK and USA. Tumour hypoxia is important because it is associated with poor response to therapy. Unfortunately, Cu[ATSM] is insoluble and has significant uptake in kidneys, liver and brain. Copper is an interesting PET element having a number of positron emitting isotopes with a variety of half-lives. The labelling chemistry is straight forward, fast and potentially suited to non-expert hands.
Method
Complexes were radiolabelled by transmetallation of the equivalent zinc complex at room temperature. Their uptake 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 on right flank.
Results
The compounds could be synthesised in good yield from an advanced common synthetic intermediate; many were soluble in water. Radiolabelling was efficient at room temperature in water. The compounds were assessed as radiochemically pure by HPLC. Cell uptake experiments showed oxygen dependant uptake over 60 minutes. The difference between oxic and anoxic uptake being greater than that observed for Cu[ATSM] in some cases. PET results showed that our most promising compounds are excreted through liver and kidneys, but that some showed considerable bladder activity within 40 minutes of injection. Tumour uptake remained good.
Conclusion
We have synthesised new structural analogues of Cu[ATSM] which show improved physical and biological properties. Their synthesis is reliable and radiolabelling is simple and quick.
