Highly-iodinated fullerene as a contrast agent for X-ray imaging
Wharton, John Timothy
Wilson, Lon J.
Doctor of Philosophy
The first fullerene-based X-ray contrast agent (CA) has been designed, synthesized, and characterized. The new CA is an externally functionalized derivative of C60 that is conceptually based on contemporary X-ray CA, all of which use iodine as the X-ray attenuating vehicle and are built on the 2,4,6-triiodinated-benzene-ring substructure. Aqueous solutions of the agents are injected intravenously via catheter into patients followed by X-ray imaging. The CA is then eliminated rapidly through the kidneys. A modified Bingel-type reaction (nucleophilic cyclopropanation) was developed in which 6 iodine atoms can be appended to C60 (per addend) to form a cyclopropane ring exclusively across one of the [6,6] double bonds of C60. Each addend contains two 2,4,6-triiodinated-benzene-ring moieties attached to a malonodiamide functionality through a nitrogen in the 5 ring position, with water-solubilizing 1,3-diol-containing serinol-benzamide substituents in the remaining ring positions (1 and 3). When the malonodiamide is reacted with C60 in excess (≥3 molar excess), however, only the fullerene monoadduct forms in good yield, with only small amounts of the diadduct detected. A general method for producing highly water-soluble, non-ionic fullerene materials was simultaneously developed. The synthetic approach also utilizes the new malonodiamide addend methodology to form multiple Bingel adducts with C60 to give C60[C(COSer)2]n (n = 4, 5, 6, Ser = 2-amino-1,3-propanediol). The compound is the most water soluble fullerene material reported to date (>240 mg C 60 mL-1). In addition, the aqueous solubility has no notable pH dependence. Due to the lack of water solubility of the amphiphilic iodinated C 60 monoadduct, the water-solubilization methodology was combined with the iodination methodology to prepare a "hybrid" material that contains both the water-solubilizing groups and the iodine containing groups. The resulting fullerene-based X-ray CA is a fully water-soluble, non-ionic pentaadduct with one hexaiodinated addend containing 8 hydroxy groups and four additional addends each containing 4 hydroxy groups. The new, first generation fullerene-based CA contains 24% iodine by weight. The ideological development of the new CA, the successful (and some of the unsuccessful) synthetic pathways and the spectral characterization of the new products is presented and discussed.
Organic chemistry; Pharmaceutical chemistry