florbenazine-f-18 and Diabetes-Mellitus--Type-1

There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2ga as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.

Topics: 5-Hydroxytryptophan; Animals; Biomarkers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Exenatide; Fluorine Radioisotopes; Humans; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Magnetic Resonance Imaging; Nerve Tissue Proteins; Positron Emission Tomography Computed Tomography; Potassium Channels; Radiopharmaceuticals; Single-Domain Antibodies; Sodium-Potassium-Exchanging ATPase; Technetium; Tetrabenazine; Tomography, Emission-Computed, Single-Photon

The vesicular monoamine transporter, type 2 (VMAT2) is expressed by insulin producing β cells and was evaluated as a biomarker of β cell mass (BCM) by positron emission tomography (PET) with [(18)F]fluoropropyl-dihydrotetrabenazine ([(18)F]FP-(+)-DTBZ).. We evaluated the feasibility of longitudinal pancreatic PET VMAT2 quantification in the pancreas in two studies of healthy controls and patients with type 1 or 2 diabetes. VMAT2 binding potential (BPND) was estimated voxelwise using a reference tissue method in a cross-sectional study, followed by assessment of reproducibility using a test-retest paradigm. Metabolic function was evaluated by stimulated c-peptide measurements.. Pancreatic BPND was significantly decreased in patients with type 1 diabetes relative to controls and the test-retest variability was 9.4%.. Pancreatic VMAT2 content is significantly reduced in long-term diabetes patients relative to controls and repeat scans are sufficiently reproducible to suggest the feasibility clinically VMAT2 measurements in longitudinal studies of new onset diabetes.

Topics: Adult; Case-Control Studies; Cell Size; Demography; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Fluorine Radioisotopes; Glucose; Humans; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Positron-Emission Tomography; Protein Binding; Tetrabenazine; Vesicular Monoamine Transport Proteins

Previous studies demonstrated the utility of [. Six HCs and four T1DM patients were scanned on separate days after injection of [. [. Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen V

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Fluorine Radioisotopes; Humans; Injections; Male; Stereoisomerism; Tetrabenazine; Vesicular Monoamine Transport Proteins; Young Adult

The ability to noninvasively measure endogenous pancreatic β-cell mass (BCM) would accelerate research on the pathophysiology of diabetes and revolutionize the preclinical development of new treatments, the clinical assessment of therapeutic efficacy, and the early diagnosis and subsequent monitoring of disease progression. The vesicular monoamine transporter type 2 (VMAT2) is coexpressed with insulin in β-cells and represents a promising target for BCM imaging.. We evaluated the VMAT2 radiotracer (18)F-fluoropropyl-dihydrotetrabenazine ((18)F-FP-(+)-DTBZ, also known as (18)F-AV-133) for quantitative PET of BCM in healthy control subjects and patients with type 1 diabetes mellitus. Standardized uptake value was calculated as the net tracer uptake in the pancreas normalized by injected dose and body weight. Total volume of distribution, the equilibrium ratio of tracer concentration in tissue relative to plasma, was estimated by kinetic modeling with arterial input functions. Binding potential, the steady-state ratio of specific binding to nondisplaceable uptake, was calculated using the renal cortex as a reference tissue devoid of specific VMAT2 binding.. Mean pancreatic standardized uptake value, total volume of distribution, and binding potential were reduced by 38%, 20%, and 40%, respectively, in type 1 diabetes mellitus. The radiotracer binding parameters correlated with insulin secretion capacity as determined by arginine-stimulus tests. Group differences and correlations with β-cell function were enhanced for total pancreas binding parameters that accounted for tracer binding density and organ volume.. These findings demonstrate that quantitative evaluation of islet β-cell density and aggregate BCM can be performed clinically with (18)F-FP-(+)-DTBZ PET.

Topics: Adolescent; Adult; Animals; Diabetes Mellitus, Type 1; Female; Fluorine Radioisotopes; Humans; Insulin-Secreting Cells; Macaca mulatta; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Tetrabenazine