Trial Information

Imaging Inducible Nitric Oxide Synthase (iNOS)Activity Using F-NOS Tracer With Positron Emission Tomography (PET) in Cellular Inflammation.

Nitric oxide (NO) is an important and unique mediator of a variety of physiological and
pathological processes. NO is generated from the oxidation of L-arginine to L-citrulline in
a two-step process by nitric oxide synthase (NOS) enzymes. In the NOS family, there are two
constitutive isozymes of NOS, neuronal NOS (nNOS) and endothelial NOS (eNOS), and one
inducible isozyme (iNOS). The three isozymes of NOS are expressed in different tissues to
generate NO for specific physiological roles. nNOS generates NO as a neurotransmitter and
neuromodulator, mainly in brain and peripheral nerve cells; eNOS regulates blood pressure,
and blood flow primarily in vascular endothelial cells. The induction of iNOS occurs by
various inflammatory stimuli (e.g., endotoxin) in activated macrophages and other types of
cells and plays a crucial role in the host defense and the inflammatory processes.

Normally, the basal level of NO in all parts of the body is very low, mainly due to the
constitutive nNOS and eNOS. In contrast, once expressed, iNOS can continue to generate NO in
large amounts (up to μM concentrations) for a prolonged period of time. Studies have shown
that production of NO by iNOS is implicated in a variety of acute and chronic inflammatory
diseases (e.g., sepsis, septic shock, organ transplant rejection, vascular dysfunction in
diabetes, asthma, arthritis, multiple sclerosis, and inflammatory diseases of the gut). iNOS
activity has also been found in many tumors. Because of the central role of iNOS in
NO-related diseases, numerous efforts have been made to develop iNOS inhibitors as
pharmaceuticals ranging from the nonselective L-arginine analogues to the selective
inhibitors reported recently. Some inhibitors of iNOS have shown promising results in animal
models of sepsis, lung inflammation, arthritis, and autoimmune diabetes. Therefore, the
development of a radiolabeled iNOS inhibitor for probing iNOS expression in vivo using
noninvasive positron emission tomography (PET) imaging will be of tremendous value to the
study and treatment of NO-related diseases.

Acute allograft rejection is the major contributor to mortality in patients receiving
orthotopic heart transplantation (OHT). Specifically, iNOS has been thought to be the main
NOS involved in producing NO that is active in acute cardiac allograft rejection.
Up-regulation of iNOS occurs in macrophage cellular infiltrates and later within the graft
parenchymal cells. In human cardiac transplantation a positive correlation has shown
between iNOS expression and left ventricular contractile dysfunction measured by
echocardiography and Doppler techniques We have recently developed a novel PET radiotracer,
[18F](+/-)NOS, designed to measure cellular iNOS activity. This study evaluates the
feasibility of the method in OHT patients undergoing surveillance endomyocardial biopsy as
part of their normal post-transplant evaluation for potential allograft rejection. More
specifically, it will compare the myocardial kinetics of this radiotracer measured by PET
with tissue measurements of iNOS measured by immunohistochemistry.