This proposal is the first competing renewal of a 3-year RO1 grant to improve the uptake of gallium-67 for tumor imaging. Uptake of Ga-67 by tumors has traditionally thought to be mediated by transferrin (Tf) and Tf receptor-dependent mechanisms. We have found that uptake of Ga-67 by cells and tumors is also mediated by a Tf-independent process, which appears more important in tumors than normal tissues. More significantly, we have shown that the Tf-independent uptake of GA in cells and tumors can be regulated. It can be specifically induced in tumors by administration of compound, which we have named """"""""nitrosipine,"""""""" which is produced when nifedipine, a commonly used dihyropyridine calcium channel blocker, is exposed to fluorescent or UV light. We have generated evidence that nitrosipine may also enhance a variety of other metal cations as well. This may expand the utility of nitrosipine for gamma scintigraphy, PET imaging and radiotherapy. We propose to apply the knowledge gained during the last funding cycle to the following 6 specific aims: 1. To define the molecular features of nitrosipine that are necessary for promoting uptake of Ga-67. 2. To confirm and define the nature of the binding of nitrosipine (or other active derivatives) to metal cations. 3. To define the biological mechanism by which nitrosipine enhances the cellular Ga-67 uptake. 4. To define the in vivo kinetics and optimal method for dosing to maximize the visualization of tumors. 5. To test how broadly effective nitrosipine, and similar active derivatives, are in promoting uptake of GA-67 in tumors of a wide variety of histologic types in a murine tumor models. 6. To explore the potential for nitrosipine or active derivatives, to enhance the uptake of Cu-64.
