Theory and Design of Relaxometric Probes

Citation

Quiñónez, Carlo Joseph (2003) Theory and Design of Relaxometric Probes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/X9G0-2M43. https://resolver.caltech.edu/CaltechETD:etd-05292003-182043

Abstract

In an effort to rationally design an apoptosis-sensitive MRI contrast agent, two novel gadolinium complexes were designed, synthesized and evaluated as components of a relaxometric probe. The first, AEDO3A will prove a useful building block for in the area of the relaxometric probe design. AEDO3A-Gd has a relaxivity of 2.2 mM-1s-1 and 3.4 mM-1s-1 at 60Mhz and 500MHz, respectively If AEDO3A-Gd is the "on" state and assuming reasonable relaxivities for the "off" state, tissue contrast modeling of the smallest-detectable relaxivity change suggests AEDO3A is suitable for incorporation into relaxometric probes.

1-(2-Aspartryl-aminoethyl)-4,7,10-tri(carboxymethyl)-cyclen (Asp-AEDO3A) is evaluated as the second component of an apoptosis-sensitive relaxometric probe system. The synthesis and characterization of the ligand and its Gd and Tb complexes is described. Fluorescence lifetime data of the terbium complex indicate the presence of 0.6 water molecules in the inner coordination sphere. The gadolinium complex has a relaxivity of 1.4 mM^-1s^-1 and 1.7 mM^-1s^-1 at 60Mhz and 500MHz, respectively. Toxicity studies demonstrated Xenopus embryos tolerated Asp-AEDO3A-Gd at magnetically useful concentrations as predicted by tissue contrast modeling. X-ray crystallography data are presented for both the ligand and gadolinium complex.

Unfortunately, no enzymatic processing of Asp-AEDO3A-Gd was observed under any conditions. This phenomenon was attributed to heretofore-unknown coordination chemistry for gadolinium elucidated from the X-ray crystal structure. This novel N-carboxamido coordination, while problematic for the application of Asp-AEDO3A-Gd as a relaxometric probe, will be potentially useful in other areas of contrast agent design.

Thesis Files