Polyiodinated Triglyceride Analogs As Potential Hepatic Imaging Agents (scintigraphy, Liver Imaging, I-125 Labeled, Computed Tomography, Triacylglycerols).

The purpose of this thesis project was to design, synthesize, and evaluate various radiologic agents for their ability to visualize small hepatic tumors and to evaluate hepatic function. Our strategy for the site-specific delivery of hepatographic agents was based mainly on a biochemical approach whereby naturally-occurring compounds known to be stored and/or synthesized in the liver serve as carriers for the radiologic probe. Therefore, on the basis of the known metabolic fate of lipids, triacylglycerols were viewed as appropriate liver-specific carrier molecules for the synthesis of hepatic-imaging agents. Accordingly, a series of (omega)-(3-amino-2,4,6-triiodophenyl)-alkanoate esters of glycerol was synthesized and evaluated in rats. The acid precursors, (omega)-(3-amino-2,4,6-triiodophenyl)-acetic and propionic acids, were synthesized by modified literature procedures. The longer-chain acid precursors were obtained by Wittig condensation of either 3-nitrobenzaldehyde with the appropriate alkylidenetriphenylphosphoran or, conversely, 3-nitrobenzyltriphenylphosphoran with an appropriate (omega)-oxoalkanoate. This afforded the respective nitrophenyl-dodecenoate and heptadecenoate esters which upon reduction, iodination and saponification gave the corresponding (omega)-(3-amino-2,4,6-triiodophenyl)-dodecanoic and heptadecanoic acids. Each of these four acids and iopanoic acid were used to esterify glyceryl 1,3-dipalmitate to furnish a series of glyceryl 1,3-dipalmitoyl 2-(omega)-(3-amino-2,4,6-triiodophenyl)-alkanoates. Similarly, esterification of 2-monopalmitin with two equivalents of each acid afforded a series of glyceryl 2-palmitoyl 1,3-di-(omega)-(3-amino-2,4,6-triiodophenyl)-alkanoates. In addition, a series of glyceryl 1,2,3-tri-(omega)-(3-amino-2,4,6-triiodophenyl)-alkanoates were prepared by esterification of the glyceryl 1,3-di-(omega)-(3-amino-2,4,6-triiodophenyl)-alkanoate intermediate or glycerol with one or three equivalents of iodinated acid, respectively. Following radioiodination with iodine-125 in a melt of pivalic acid, the radiolabeled derivatives were evaluated in rats for their ability to selectively localize in the liver. Of the 19 target compounds synthesized and evaluated, glyceryl 1,2,3-tri-3-(3-amino-2,4,6-triiodophenyl)-propanoate displayed rapid and sustained liver specificity. This agent was found to accumulate in the liver in concentrations of 67, 75, and 86% of the administered dose at 5 min, 30 min, and 24h, respectively. Moreover, the 24h liver to blood ratio of 235 was the most impressive of all compounds evaluated. Based on these preliminary results, further preclinical scintigraphic and CT studies in higher animal species are warranted with this agent.PhDPharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127781/2/8521009.pd