Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Medical Biophysics

Supervisor

Savita Dhanvantari

Abstract

Cardiovascular disease affects 1.6 million Canadians, of whom one-third have heart failure (HF). HF is diagnosed by imaging investigations and detection of circulating biomarkers. Most of the current imaging strategies study morphologic and gross functional changes, but fall short of imaging molecular abnormalities associated with HF. Biomarkers offer molecular targets; however, clinical biomarkers circulate systemically and are not cardiac-specific. Thus, there is critical need for a biomarker that is endogenous to myocardial tissues. The growth hormone secretagogue receptor 1a (GHSR1a), which binds the hormone ghrelin, is expressed by cardiomyocytes and is elevated in HF patients. This study characterized the specificity of the novel tracer [1-Nal4, Lys5(4-[18F]-FB)]G-7039 to target GHSR1a using Positron Emission Tomography (PET). In vitro analysis of probe specificity by cellular uptake determined that binding was independent of receptor expression, which was confirmed by in vivo PET imaging in GHSR1a-wildtype (wt) and -knockout (ghsr-/-) mice. Ex vivo biodistribution comparing specificity and effects of nutritional state showed that [1-Nal4, Lys5(4-[18F]-FB)]G-7039 did not distribute to the heart and uptake was independent of circulating ghrelin levels. Although [1-Nal4, Lys5(4-[18F]-FB)]G-7039 demonstrated in vitro stability, negligible cardiac uptake and high uptake in the liver, intestines and kidneys within 1 h post-injection indicated rapid probe elimination through hepatobiliary and renal echanisms, possibly explained by a highly lipophilic tracer. Analysis of cardiac GHSR1a expression and metabolic markers by fluorescence microscopy in fasted, fed, wt and ghsr-/- mice suggests that there may be a ghrelin/GHSR1a system in the heart that is regulated independently of systemic ghrelin/GHSR1a, and that GHSR1a does not play a significant role in cardiac metabolism in healthy mice. In vitro stability and cellular uptake, ex vivo iodistribution and in vivo imaging conducted in this study present a step towards characterizing a suitable GHSR1a PET tracer that may be used to detect HF.

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