We have synthesized and evaluated five series of polymeric gadolinium chelates which are of interest as potential MRI blood pool contrast agents. The polymers were designed so that important physical properties including molecular weight, relaxivity, metal content, viscosity, and chelate stability could be varied. We have shown that, by selecting polymers of the appropriate MW, extended blood pool retention can be achieved. In addition, relaxivity can be manipulated by changing the polymer rigidity, metal content affected by monomer selection, viscosity by polymer shape, and chelate stability by chelator selection.

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' butyramide group resulted in a nanomolar potent and selective HNC inhibitor as well as a dual HFS/HNC inhibitor. Benzylic ethers with a four- or five-carbon methylene linker in the P1' position also produced nanomolar potent HFS/HNC inhibition and micromolar potent HFC inhibition as expected. Surprisingly, the phenolic ethers of the same overall length as the benzylic ethers showed nanomolar potencies against HFC, as well as HFS and HNC. The potency profile of the phenolic ethers was optimized by structure-activity relationships of the phenolic group and the C-terminal amide. These inhibitors may help elucidate the in vivo roles of matrix metalloproteinases in normal and disease states.

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Our continued research on the use of heavy metal cluster complexes as a new class of X-ray contrast agents in medical diagnostic imaging is described. A series of 2:3 cluster-ligand complexes, [(W(IV)3SO3)2L3]4- (L = linear polyaminopolycarboxylate ligands), were isolated from the reaction of aqua ion [W(IV)3SO3(H2O)9]4- (prepared in large quantities through an improved literature process) with respective ligands in refluxing DMF. The salts of [(W(IV)3SO3)2L3]4- complex anions were fully characterized using routine techniques such as elemental analysis, MS, HPLC, UV-vis, IR, and NMR. The solid structures of two complex anions, [(W(IV)3SO3)2(PDTA)3]4- and [(W(IV)3SO3)2(HO-PDTA)3]4-, were determined by X-ray crystallography. They are the first examples wherein two W(IV)3SO3 clusters are complexed and linked by three ligands that contain two terminal iminodiacetate (bis-IDA) groups. Complexation of the unstable aqua ion [W(IV)3SO3(H2O)9]4- with ligands has imparted desired biological compatibility to the tungsten metal cluster. These complexes are stable and highly soluble in H2O. The potential utility of such tungsten cluster complexes as X-ray contrast agents was evaluated in both in vitro and in vivo animal studies. In addition, the syntheses of several new linear polyaminopolycarboxylate ligands used in this study are reported.

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