Optimized Relaxivity and Stability of [Gd(H(2,2)-1,2-HOPO)(H₂O)]^- for Use as an MRI Contrast Agent¹

Abstract

Relaxometry and solution thermodynamic measurements show that Gd-H(2,2)-1,2-HOPO is a good candidate as a contrast agent for Magnetic Resonance Imaging (MRI-CA). Acidic, octadentate H(2,2)-1,2-HOPO forms a very stable Gd(III) complex [pGd 21.2 (2)]. The coordination sphere at the Gd(III) center is completed by one water molecule that is not replaced by common physiological anions. In addition, this ligand is highly selective for Gd(III) binding in the presence of Zn(II) or Ca(II).The symmetric charge distribution of the 1,2-HOPO chelates is associated with favorably long electronic relaxation time T 1,2e comparable to those of GdDOTA. This, in addition to the fast water exchange rate typical of HOPO chelates improves relaxivity to r 1p = 8.2 mM −1 s −1 (0.47 T). This remarkably high value is unprecedented for small molecule, q = 1 MRI-CA.

Stability and Toxicity of Contrast Agents

“…A series of tripodal heptadentate ligands containing tris(aminoethyl)amine scaffold and three HOPO and more recently terephthalamide (TAM) moieties as coordinating units were developed by Raymond and co-workers and suggested as MRI contrast agents (Chart 4.4). Later, similar ligands based on ethylenediamine and cyclen ( [12]aneN 4 ) scaffolds and 1,2-HOPO and 2-hydroxybenzamide coordinating groups were also synthesized and studied [65,66]. Ligands containing HOPO moieties for Gd 3+ complexation offer the advantage of high relaxivities due to the increased number of inner-sphere water molecules in the Gd 3+ complexes (q = 2 or 3).…”

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

“…30 The validity of the relaxometric evaluation of the hydration number has been confirmed through the direct measurement of q by luminescence in the case of EuTACN-1,2-HOPO (q = 3) 33 and Eu-H(2,2)-1,2-HOPO (q = 1). 39 The NMRD profile fits for the 4 conjugates were obtained by fixing q to 2. Although the hypothesis that both conjugated complexes possess q=1 cannot be excluded on the basis of the relaxometric data, the assumption of two bound water molecules gave the best fits (Supporting information Figure S1) for both the internally and externally modified capsids, and is consistent with other TREN-bis-HOPO-TAM derivatives.…”

1,2-Hydroxypyridonates as Contrast Agents for Magnetic Resonance Imaging: TREN-1,2-HOPO

“…TREN-1,2-HOPO 15 and 3-benzoxy-4-carboxy-2-pyridone (3,2-HOPO(Bn) acid) 5 were synthesized as previously reported. 1 H and 13 C NMR spectra were obtained on Bruker AVQ-400 spectrometers and are reported in ppm.…”

“…Zn(II) and Ca(II) are the most abundant metals in this respect, since the concentrations of uncomplexed Zn(II) (10-15 µM) and Ca(II) (0.4 -2.5 mM) in serum are sufficient for release of lethal amounts of Gd(III) (~20 µM). 1 The selectivity of TREN-1,2-HOPO for Gd(III) over Zn(II) and Ca(II) was determined by comparing the conditional stability constants pGd and pZn or pCa with those for the benchmark compound DTPA (pGd-pZn = 4.2; pGd-pCa = 11.7).…”