SPECIFIC AIMS To date, in vivo measurement of beta cell mass (BCM) is an unmet clinical need that, if possible, would allow tracking and monitoring of recent advances in therapies designed to preserve BCM1 and/or monitor transplanted beta cells.2 Beta cell loss occurs in the endocrine pancreas resulting in loss of insulin secretion and subsequent onset of diabetes. Current clinical in vivo measurements of beta cell function (e.g., C-peptide release in response to oral glucose tolerance test (OGTT)) may underrepresent total BCM due to variability in beta cell function in response to glucose. Beta cells and neurons share common cellular transporters and receptors, and with this in mind, we previously screened potential positron emission tomography (PET) neuroradioligands, already approved for use in humans, to image BCM. From this effort, we published two previous studies demonstrating the potential utility of [11C](+)-PHNO (D2/D3 receptor agonist) to differentiate healthy controls and individuals with type 1 diabetes (T1D).3,4 Dopamine is synthesized within beta cells and co-released with insulin and both D2 and D3 receptors have been shown to regulate insulin secretion.5,6 Interestingly, four of the individuals with T1D that had no measurable C-peptide release had measurable proinsulin and uptake of [11C](+)-PHNO,4 possibly suggesting a subset of not fully functional beta cells, as has been shown previously with proinsulin.7–9 In addition, we found a significant positive correlation of age-at-diagnosis and [11C](+)-PHNO uptake. Previously, age-at-diagnosis has been interpreted to reflect severity of disease (e.g. more severe beta cell loss in younger individuals).9–11 We also performed preliminary immunofluorescence in a healthy control and T1D pancreas.4 We found colocalization of both D2 and D3 receptors with insulin in the healthy pancreas while there was no colocalization with glucagon, somatostatin, and polypeptide Y. In the T1D pancreas, no staining of insulin or dopamine receptors was found, suggesting [11C](+)-PHNO radioligand is binding to D2/D3 receptors on only beta cells. In a preliminary analysis, we recently used state-of-the art proteomics to successfully identify 5382 islet proteins derived from tissue of a single healthy human islet donor; of which at least 200 are categorized as known islet proteins. We used pathway analyses in this sample and found multiple beta cell networks and beta cell-unique proteins associated with our proposed radioligand: D2/D3 receptors. Additional ex vivo human pancreas and islet studies are required to further characterize uptake of [11C](+)-PHNO in human beta cells and fits well within the Human Islet Research Network - Human Pancreas Analysis Consortium (HIRN-HPAC) mission. Evidence of both functional and non-functional BCM has been demonstrated in previous immunohistochemistry characterizations of T1D individuals;10,11 however, similar studies, with the addition of dopamine receptor (D2/D3) immun...