Zinc(II) Sensitive MRI Contrast Agents as Diagnostic Sensors for Tracking Insulin Secretion

ABSTRACT SignificanceDiabetes mellitus typeT Dand particularly typeT Dandgtof casesare becoming an increasing burden on socioeconomic resources with vastly increasing patient numbers all over the worldInsulin dependent treatment regimen such as regular insulin injections are well established for both T D and T D but have been associated with a negative impact on the quality of life of patients with a variety of longterm complicationsApart from insulin administration that represents the standard treatment regimen for T Dmore typical treatment options for T D involve administration of oral antihyperglycemic drugse gmetformin or acarboseCurrent and future research fields focus on the search for insulin independent treatment optionsThis importantalbeit elusivescientific goal has been pursued for overyearswith promising results particularly in the field of pancreatic islet transplantationHeregrafting of either entire cadaveric pancreases or encapsulated islets comprised of insulin producing beta cells in a protective capsule has been the main focus of researchHoweverone major drawback in the grafting success of pancreatic tissue or islets is the monitoring process to quantify insulin secretion of the graft upon transplantationAn imaging technique that could be adapted to gain quantitative information on the insulin secretionideally in a minimally invasive fashionmay be invaluable for the future success of islet pancreas transplantationFurthermoresuch a technique could also be used in order to quantify insulin secretion and to determine the onset of TDor TDtherefore providing diagnostic information on the progression and etiology of diabetesHypothesisWe hypothesize that the use of zinc IIsensitive MRI contrast agents offers the ability to solve these therapeutic and diagnostic problemsIn particularwe have already shown that this sensor type exhibits high efficacyhigh selectivity and low toxicity when used in small animals or even in primatese grhesus macaquePreliminary DataWe have demonstrated that this molecular sensor type represents the vanguard of zinc IIsensitive MRI contrast agents with the ability to sensitively image insulin secretion in vivo using different animal speciesincluding micerats and primatesThe preliminary results obtained will be crucial for the further development of this technology in the screening of transplanted islets or whole pancreatic tissueSpecific AimsThe key objectives in Phase I entail the synthesispurification and characterization of a large amount of CPand other structurally similar analoguesPhase IAimsandAll compounds will be used in Phase II for advanced studies on stabilityphysical properties and biodistributionThe most efficient sensor species will be used for toxicity studies in preparation for submission of an IND to receive approval for a first in human clinical trialPhase IIAimFurthermorethe most effective compound will be used to quantify insulin secretion in extracted islets in vivo via transplanted pancreatic tissue in nude micePhase IIAimFinallyhealthy rats as well as a T D and T D rat model using Sprague Dawley rats will be used for pancreatic imaging over the course of weeks to monthsCommon anti hyperglycemic drugse gLiratuglidewill be administered in the T D model to assess drug efficacy using our sensorsPhase IIAimOverall ImpactTaken in concertthe technologies developed by VitalQuan will be made available to clinical labs and companies developing new methods and technologies to improve islet graft successOur agents will also provide direct measures of oscillating phaseversus phaseinsulin secretion and will therefore offer an invaluable tool for those companies currently developing advanced pharmaceuticals that promote or enhance insulin secretionFurthermorethe use of our agents will also help to establish unprecedented studies designed for in vivo insulin trackingTaken in concertthese applications will accelerate the commercialization of such MRI contrast agents for clinical use in diabetes research and treatment NARRATIVE Diabetes is a chronic disease affecting millions of people in almost every part of the worldVarious scientists around the globe are trying to develop methods to treat diabetes that do not require regular insulin injections but a variety of obstacles associated with these efforts eventually limit their successVitalQuan is developing technologies that provide valuable diagnostic information in order to overcome these drawbacksUltimatelysuch technologies will improve the outcome of diabetes treatments