The goals of this project are to use cyclotron produced and generator produced PET isotopes to label and evaluate novel tracers to measure parameters of cardiac physiology. Iodine-122 (3.6 min half-life) quaternary amines are attractive for rapid, repeat PET blood flow studies. 122I will be produced from a 122Xe/122I generator system and used in rapid synthetic chemistry to produce the labeled quaternary amines. We will pursue the iodine-125 labeling of three classes of quaternary amines (pheny1 trimethy1 ammonium ion, iodobenzylguanidine and piperazinium ion) as potential cardiac flow agents and assess their feasibility for 122I labeling as well as evaluate their potential imaging characteristics in the red blood cell perfused rabbit heart under normal, ischemic and hypoxic conditions. Promising tracers will be labeled with 122I for in vivo imaging studies in project I. Additionally, we also intend to begin work on a fully automated generator/chemistry system relying on the latest in automation technology to show the viability of this generator as a suitable alternative for radiotracer production. A considerable body of evidence exists implicating mitochondrial loss or dysfunction in cardiomyopathies and normal aging processes of the heart. The loss of mitochondrial density and function in the heart has been correlated with mutations in the mitochondrial DNA. Studies in young and ld rats have demonstrated that the lost of electron transport chain enzymatic function increases with age. Thus, a non-invasive imaging agent to measure mitochondrial density and function would greatly enhance our ability to define the loss of activity as well as contribute to the understanding of the pathophysiology of cardiomyopathies and aging. We propose to evaluate two classes of mitochondrial probes, rotenones and rhodamines, labeled with fluorine-18 and carbon-11. Specifically, we will study the uptake and retention of these tracers in isolated mitochondria and cultured liver cells. Rotenones: block the complex I with rotenone and measure uptake versus NADH and citrate synthetase activity. Rhodamines: measure uptake in whole cells versus media additives such as ouabain, CCCP and nigericin (modulators of membrane potentials). A similar set of experiments in the buffer perfused isolated rat heart will be performed. We will use the red blood cell perfused rabbit heart to define the tracer uptake and washout kinetics under normal, ischemic and hypoxic conditions. We will use an occlusion/reperefusion rabbit model to correlate tracer uptake with measures of mitochondrial density and function. The anticipated results from this project will be: I) the development 122I quaternary amines as flow tracers and the improvement of the 122I chemistry with automation of the generator system. ii) the development of mitochondrial probes for the degenerative loss of electron transport function provided we can show that these agents are not merely extracted and retained as a function of flow.
Showing the most recent 10 out of 55 publications
