Highly-iodinated fullerene as a contrast agent for X-ray imaging

摘要

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.