THE LONG-TERM OBJECTIVE OF THE PROPOSED PROGRAM IS TO DEVELOP PARAMAGNETIC PHARMACEUTICAL PRODUCTS THAT ARE SAFE AND EFFECTIVE FOR IMPROVING THE DIAGNOSTIC YIELD OF MAGNETIC RESONANCE IMAGING.

THE LONG-TERM OBJECTIVE OF THE PROPOSED PROGRAM IS TO DEVELOP PARAMAGNETIC PHARMACEUTICAL PRODUCTS THAT ARE SAFE AND EFFECTIVE FOR IMPROVING THE DIAGNOSTIC YIELD OF MAGNETIC RESONANCE IMAGING. SPECIFIC AIMS ARE TO DEVELOP SYNTHETIC ROUTES TO STABLE CHELATES BEARING FUNCTIONAL GROUPS THAT ALLOW THEIR COVALENT ATTACHMENT TO A VARIETY OF BIOMOLECULES. METHODS OF EVALUATION INCLUDE PURITY TESTS, COMPOSITIONAL ANALYSIS, IN VIVO AND IN VITRO ASSAYS OF STABILITY, MEASUREMENTS OF RELAXIVITY, SCREENING TOXICITY EVALUATION, AND MAGNETIC RESONANCE IMAGING. PHASE I STUDIES WILL FOCUS ON THE PARAMAGNETIC METAL CATIONS, IRON (III) AND GADOLINIUM (III), AND ON COORDINATING MOIETIES THAT FAVOR THESE METALS. LIGANDS WITH HIGH AFFINITY AND SPECIFICITY FOR IRON (III) HAVE BEEN DEVELOPED PREVIOUSLY BUT ARE LARGELY UNSTUDIED FOR MAGNETIC RESONANCE APPLICATIONS. PHASE I STUDIES WILL UTILIZE IRON-AVID LIGANDS AND WILL ATTEMPT DERIVATIZATION TO PERMIT BIOMOLECULAR CONJUGATION, THE LATTER APPLICABLE TO PROTEIN, CARBOHYDRATE, OR LIPID SUBSTRATES. PHASE I RESULTS ARE EXPECTED TO INCLUDE: A.SELECTION OF SEVERAL NONTARGETED CHELATES SUITABLE B.ESTABLISHMENT OF OPTIMAL, GENERIC METHODS FOR PRODUCTION OF ""TARGETED''CHELATES. DURING PHASE II, PRECLINICAL AND CLINICAL PHARMACEUTICAL TESTING WILL BE THE HIGHEST PRIORITY. ADDITIONALLY, PARAMAGNETIC CONJUGATES OF BIOMOLECULAR CARRIERS PREPARED USING PHASE I METHODOLOGY WILL BE TESTED. THE SELECTION OF LIGANDS AND APPROACH TO SYNTHETIC DERIVATIZATION ARE INNOVATIVE; COMMERCIALIZATION OF IMPROVED AGENTS WITH BROAD APPLICATION WILL BE ADVANCED.