Student: George Firth
The aim is to develop methodology for production of radionuclides and tracers to support a programme of study on use of PET to help understand changes in trafficking of essential trace metals (Zn, Cu, Mn, Fe) in diseases where they are highly relevant, such as diabetes, cancer, dementia and pulmonary hypertension. The objectives will be (a) to set up Zn-63 production at KCL (Cu-64/62 already implemented at KCL; Fe-52 and Mn-52 purchased externally; Zn-62 production already in place); (b) develop suitable delivery vehicles e.g metastable lipophilic complexes, ionic salts, protein bound (albumin, transferrin)and routes to control trafficking of the metals via endogenous transport, retention and excretion mechanisms; (c) use them to map normal trafficking of Cu, Zn, Fe, Mn in mice, (d) map changes in trafficking in disease models, and (e) identify translational opportunities for human PET studies.
Trafficking of essential trace metals (e.g. zinc, copper, iron, manganese) is abnormal in diseases such as diabetes, cancer (e.g. pancreatic, prostate, melanoma, breast), and dementia1 (e.g. Alzheimer’s, Fig. A), but these changes are scarcely understood. Examples from the work of the current group of collaborators include changes in copper, zinc and iron trafficking in brain in dementias Fig. A)1 zinc in diabetes2-4 and pulmonary hypertension,5 while others have identified changes in copper and zinc handling in prostate cancer, melanoma, glioblastma and other cancers.
A new opportunity to study these changes using PET is now afforded by availability of positron-emitting radiometals. This project will develop tools to exploit radioisotopes of copper (Cu-64, half-life 12 h), zinc (Zn-63, 30 min), iron (Fe-52, 8.3 h) and manganese (Mn-52, 5.5 days) to image trace metal transport in normal animals and animal models of cancer, diabetes, dementia and other disease to identify changes in trafficking, in relation to gene expression changes measured by conventional molecular and proteomic methods, as a prelude to human PET imaging. As well as PET it will be supported by new infrastructure afforded by the recently funded Multi-user Equipment Grant from Wellcome Trust: The London Metallomics Facility (PI: Blower), a joint initiative between King’s and Imperial.