This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-DK-101: """"""""Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NINDK"""""""". Loss of insulin producing cells in the pancreatic islets, the endocrine component of pancreas, referred as beta cell mass (BCM), leads to an inability to manage blood sugar levels. This results in diabetes mellitus (DM), type 1 (TIDM) or type 2 (T2DM). T1DM, has previously been known as """"""""insulin-dependent diabetes mellitus,"""""""" (IDDM) or """"""""juvenile diabetes."""""""" TIDM is a life-long condition in which the pancreas stops making insulin due to loss of BCM from an autoimmune response. T2DM, previously known as """"""""noninsulin-dependent diabetes mellitus"""""""" (NIDDM) or """"""""adult-onset diabetes"""""""", is the most common form of diabetes. About 90 to 95 percent of people who have diabetes have T2DM. There are 23.6 million people in the United States, or 8% of the population, who have diabetes. The total prevalence of diabetes increased 13.5% from 2005-2007 according to the American Diabetes Association. Despite rigorous control of blood sugar, the majority of diabetic patients develop serious late-stage complications including retinopathy, nephropathy, neuropathy, microangiopathy and strokes. A long asymptomatic preclinical period characterized by gradual BCM loss precedes clinical T1DM. Methods to predict the development of clinical T1DM currently rely on the detection of multiple autoantibodies to islet- associated proteins combined with HLA genotyping. Improvement of the power and reliability of methods to predict diabetes would raise the possibility for pharmacological intervention during the preclinical phase and the honeymoon period to either slow down or arrest the ongoing destruction of the remaining ?-cells. It will also allow the monitoring and management of islet transplantation and help the development of immunosuppressive therapies. A non-invasive imaging approach to monitor BCM would enable earlier and better diagnosis/management of both TIDM and T2DM since pancreas is not an ideal organ for biopsy. Several groups have described non- invasive imaging approaches to detect and follow loss of BCM. Various radiotracer methods are currently underway to study differential pancreatic uptake include 6-deoxy-6-125I-iodo-D-glucose, 3H-monosaccharide D- mannoheptulose, 3H-glibenclamide, 2-14C-alloxan, 11C-acetate, 11C-methionine and 18F-FDG. Recently vesicular monoamine transporter-2 in pancreatic beta cells and in sympathetic nerve terminals that innervate islets and exocrine pancreas, was targeted using the specific radioligand 11C-DTBZ. 18F-FDOPA was used to diagnose infants with congenital hyperinsulinism. The ability to diagnose insulin-related disorders is in great need and the various approaches reported thus far have limitations in their ability to detect changes in BCM. Dopamine D2/D3 receptor expression have recently been demonstrated on rodent and human ?-cells using isolated islets and beta cell lines. These receptors are present in pancreatic islets where they co-localize with insulin producing granules and may serve as a surrogate marker for imaging alterations in BCM. We have used 18F-fallypride, a high affinity D2/D3 PET imaging agent for the study of islet cells and BCM in rodent pancreas with promising results. 18F-Fallypride binds to pancreas sections and isolated islet cells and is competed off by haloperidol, a D2/D3 inhibitor, indicating specific binding. Depleting ?-cells by treatment with streptozotocin reduced 18F-fallypride binding by 70% and immunostain for insulin confirmed ?-cell loss. Following IV 18F- fallypride administration, ex-vivo microPET imaging reveals 18F-fallypride in the pancreas. In order to maximize visualization of the pancreas (allowing clearance from adjacent organs) and monitor transplanted islet cells we propose in this application to develop 124I-epidepride (124I-EPID) (t1/2 124I=4.2 days) which will allow imaging over extended periods compared to 18F-fallypride (t1/2 18F=0.076 days). 124I-Epidepride is a new radiotracer suitable for extended imaging of dopamine D2/D3 receptors and may have applications in monitoring of ?-cell-loss in DM and provide tools to measure responsiveness to new therapies and evaluate efficiency of islet graft survival. PHS 398/2590 (Rev. 09/04)
This is a challenge request for developing a noninvasive PET imaging agent for the study of diabetes. Diabetes Mellitus is a major health problem currently affecting the US. The proposed approach will help in the management of this patient population. This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-DK-101: """"""""Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NINDK""""""""
