DEVELOPMENT OF PET AGENTS FOR IMAGING APOPTOSIS

University Of California San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

Description: (provided by applicant) The overall goal for this Pilot Project is the development of new imaging agents for the in vivo detection of apoptosis in cancerous tumors following anti-ErbB-based therapeutic intervention, The induction of apoptosis is thought by many to be an essential factor in the control and ultimate death of tumors via radio. or chemotherapy. Resistance by cancer cells to these therapeutic interventions has been attributed to the expression of a family of anti-apoptotic agents that allow the cells to survive the induction of cell death. The process of apoptosis starts with the activation of specific intracellular cysteine proteases called caspases. Once initiated, a further sequence of events occurs that includes the disruption and blebbing of cellular membranes, and the fragmentation of the cellular DNA with condensation of the nucleus, all culmination in the shrinkage and then the total disruption of the cell. The goal of this project is to develop radiotracers that can image tissue undergoing apoptosis. The specific radioligands to be studied are analogs of the DNA-binding dyes currently used for monitoring apoptosis in cells, and radiolabeled antibody fragments (scFv) that target phosphatidylserine found on the outer plasma membrane during apoptotic disruption of the cell. These analogs will be synthesized and radiolabeled in the Center for Functional Imaging. The radioisoptopes used for the labeling of these agents will be positron emitters (11C, 18F, possibly 124I, 76Br), so that Positron Emission Tomography (PET) can be used as the imaging modality. Once prepared, the binding characteristics of these new tracers will be examined using human cancer cell lines treated with anti-ErbB agents used to induce apoptosis. Those agents exhibiting the best affinity, selectivity and metabolic stability will be tested further in animal xenograft tumor models to examine the biodistribution of these agents in vivo. Those with sufficient uptake and clearance will be used in longitudinal PET studies to examine their potential as imaging agents. Ultimately these agents will hopefully be used in human cancer patients.