1,2-Hydroxypyridonate/Terephthalamide Complexes of Gadolinium(III): Synthesis, Stability, Relaxivity, and Water Exchange Properties

Abstract

Four new Gd(III) complexes based on the 1,2-hydroxypyridinone chelator have been synthesized and evaluated as potential MRI contrast agents. Previously reported work examining Gd-TREN-1,2-HOPO (3) suggests that the 1,2-HOPO unit binds strongly and selectively to Gd(III), encouraging further study of the stability and relaxivity properties of this class of compounds. Among the new complexes presented in this paper are the homopodal Gd-Ser-TREN-1,2-HOPO (Gd-5) and three heteropodal bis-1,2-HOPO-TAM complexes (Gd-6, Gd-7, and Gd-8). Conditional stability constants were determined and all pGd values are in the range of 18.5 − 19.7, comparable to other analogous HOPO complexes and currently used commercial contrast agents. Relaxivities for all complexes are about twice those of commercial agents, ranging from 7.8 − 10.5 mM −1 s −1 (20 MHz; 25 °C), and suggest two inner-sphere water molecules in fast exchange. Luminescent measurements were used to verify the number of coordinated waters for Gd-5, and VT 17 O NMR experiments were employed for the highly soluble Gd-TREN-bis-1,2-HOPO-TAM-N3 (Gd-8) complex to measure a fast water exchange rate, 298 k ex = 1/τ M , of 5.1(±0.4) × 10 8 s −1 ( 298 τ M ∼ 2 ns).

Stability and Toxicity of Contrast Agents

“…Nevertheless, 1,2-HOPO derivatives are still considered in ligand design as illustrated by the example of the highly basic heteropodal bis-HOPO-TAM ligands obtained through the combination of two 1,2-HOPO moieties and one TAM residue on a tris(aminoethyl)amine scaffold. As expected, the Gd 3+ complexes have two inner-sphere water molecules in fast exchange and consequently have been proposed as high relaxivity MRI contrast agents [67]. The total basicity (log β 01i = log K i H ) of the tripodal ligands is in the range of log β = 20-30, similar to that of DTPA and DOTA, although it should be noted that direct comparison of the log β 01i .values of the ligands listed in Table 4.2 with those of the traditional polyaminopolycarboxylate ligands is not meaningful because log β 01i of the tripodal ligands involves the protonation of the capping N-atoms, which do not participate in coordination with the Gd 3+ .…”

Pyrone derivatives and metals: From natural products to metal-based drugs

“…This novel Gd complex was superior to commercial contrast agents in clinical use, both in terms of stability and relaxivity [99]. In order to optimize these parameters, the linker was varied [97] and the coordinating pyridonates were partly replaced with terephthalamide [100]. Compounds with two [101] or three [97] water molecules in the inner coordination sphere proofed successful in in vivo assays [102].…”

Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes

“…In addition, an introduction of TAM moiety adds another functional group not coordinated to metal ion and such ligands are bifunctional; another ligand modification can be introduced through the TAM second carboxylic group. As thiazoline amides are not very reactive to amines, a selective reaction with just one or two amino groups of TREN is possible with a reasonable yield; the introduction of, for example, 1-Me-2,3-HOPO or 1,2-HOPO units has been done under high-dilution conditions and with a very slow addition of thiazoline amide into the amine solution [382,385,387]. The TAM unit can be introduced to the last TREN nitrogen atom in two ways.…”

“…In the first case, the TAM-thiazoline bis(amide) is reacted with disubstituted and protected TREN derivative leaving the other TAM-thiazoline amide group accessible for next reaction with amine-containing molecules. A number of derivatives have been synthesized by this way; they involve TREN-bis(HOPO)-mono(TAM) ligands modified with polyethyleneglycol chains of different lengths [386][387][388], a (2-amineoxo)ethyl substituent [389] (Scheme 3.72) or chains with free amine group(s) [387]. The other approach is based on reaction of one thiazoline amide group with amine-containing molecules followed by reaction with the double substituted TREN derivative [386,387].…”

“…A number of derivatives have been synthesized by this way; they involve TREN-bis(HOPO)-mono(TAM) ligands modified with polyethyleneglycol chains of different lengths [386][387][388], a (2-amineoxo)ethyl substituent [389] (Scheme 3.72) or chains with free amine group(s) [387]. The other approach is based on reaction of one thiazoline amide group with amine-containing molecules followed by reaction with the double substituted TREN derivative [386,387]. The last TREN amino group can also be substituted by acid form of TAM employing the standard peptide coupling chemistry through active esters and reagents as O-(7-azabenzotriazol-1-yl)-N,N,N ,Ntetramethyluronium hexafluorophosphate (HATU); similarly, the free carboxylic acid group of protected TREN-bis(HOPO)-mono(TAM) intermediates can be modified with the amines.…”