Radioiodination via isotope exchange in pivalic acid

A variety of benzoic and aryl aliphatic mono and polyiodinated acids and esters (sterol, triglyceride) were radioiodinated in 55-99% radiochemical yield by isotope exchange with Na 125I in a melt of pivalic acid. In general, the reaction was complete in 1 h at 155[deg]C with little or no substrate decompostion. High specific activity studies afforded 125I-labeled iopanoic acid with a specific activity of over 700 Ci/mmol.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26445/1/0000533.pd

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.Ph.D.Pharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127781/2/8521009.pd

Formulation of Polyiodinated Triglyceride Analogues in a Chylomicron Remnant-Like Liver-Selective Delivery Vehicle

Purpose . A formulation methodology for the incorporation of polyiodinated triglyceride (ITG) analogues into a protein-free chylomicron remnant-like emulsion was developed to provide a vehicle for the selective hepatic delivery of these agents for contrast-enhanced X-ray computed tomography (CECT).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41452/1/11095_2004_Article_306640.pd

Radioiodinated Cholesteryl lopanoate as a Potential Probe for the in Vivo Visualization of Atherosclerotic Lesions in Animals

Radioiodinated cholesteryl iopanoate, a nonhydrolyzable cholesteryl ester probe, showed increased uptake into atherosclerotic aortas of cholesterol-fed rabbits in comparison with normal rabbits. Auto-radiography of the aortas showed the radioactivity to be concentrated in areas of visible atherosclerotic involvement. Lipid extraction and thin-layer chromatography of this tissue as well as liver, adrenal, and plasma confirmed the resistance of this probe to hydrolysis. These findings suggest that 125 I-cholesteryl iopanoate may prove useful for noninvasively monitoring atherosclerosis in intact laboratory animals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41511/1/11095_2004_Article_306434.pd

Breast Cancer Imaging Using the Near-Infrared Fluorescent Agent, CLR1502

Positive margins after breast conservation surgery represent a significant problem in the treatment of breast cancer. The near-infrared fluorescence agent CLR1502 (Cellectar Biosciences, Madison, WI) was studied in a preclinical breast cancer model to determine imaging properties and ability to detect small islands of malignancy. Nude mice bearing human breast cancer flank xenografts were given a systemic injection of CLR1502, and imaging was performed using LUNA (Novadaq Technologies Inc., Richmond, BC) and Pearl Impulse (LI-COR Biosciences, Lincoln, NE) devices. Normal tissues were examined for fluorescence signal, and conventional and fluorescence histology was performed using the Odyssey scanner. Peak tumor to background ratio occurred 2 days after injection with CLR1502. The smallest amount of tumor that was imaged and detected using these devices was 1.9 mg, equivalent to 1.9 × 106 cells. The highest fluorescence signal was seen in tumor and normal lymph node tissue, and the lowest fluorescence signal was seen in muscle and plasma. Human breast cancer tumors can be imaged in vivo with multiple optical imaging platforms using CLR1502. This pilot study supports further investigations of this fluorescent agent for improving surgical resection of malignancies, with the goal of eventual clinical translation