Rationally designed bifunctional bisphosphonates for the detection and radionuclide therapy of bone metastases


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Rafael Torres Martin de Rosales1, Ciara Finucane2, Steven J Mather2, Philip J Blower1

1King's College London, UK, 2Institute of Cancer, Barts and The London School of Medicine, UK

Abstract

Background

99mTc-methylenebisphosphonate (99mTc-MDP) is the most used radionuclide tracer for the detection of bone metastases. This agent accumulates in highly metabolic areas of the bone such as metastases due to the targeting properties of the bisphosphonate (BP) group. A therapeutic analogue, the beta-emitter 188Re-HEDP, has shown great promise as a palliative and therapeutic agent in recent clinical trials. Despite their proven clinical success, however, it is known that both the 99mTc-MDP and 188Re-HEDP preparations used in the clinic are not chemically pure, consisting of a mixture of unknown anionic polymers. Furthermore, the therapeutic 188Re-BPs are unstable in vivo, leading to reduced bone uptake and high soft tissue doses.

Aim

There is a need for rational design of 188Re-BP derivatives to improve specificity and reduce soft tissue and bone marrow doses during radionuclide therapy. Our aim is to achieve this by using novel stable and well-designed bifunctional targeted agents.

Results

A series of new BP-chelator based on pamidronate, alendronate and neridronate have been designed, synthesised, purified and characterised. These compounds have been radiolabelled with 99mTc in excellent radiochemical yields and purity. In vitro experiments have revealed that these compounds show higher and more selective binding to the main component of bone mineral (hydroxyapatite) and less protein binding than 99mTc-MDP. NanoSPECT studies with Balb/C female mice have also demonstrated a remarkably similar biodistribution profile compared with 99mTc-MDP.

Conclusion

These results demonstrate the high potential of our BP-chelators conjugates as well-defined and characterised agents for the diagnosis and treatment of bone metastases. Biological evaluations with 188Re analogues are underway to assess the prospects for improving radionuclide therapy by this approach. These results will be presented.

Acknowledgements

We would like to thank Cancer Research UK (Grant C789/A7649) for funding