Redox-active Magnetic Resonance Imaging Contrast Agents: Studies with Thiol-bearing 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetracetic Acid Derivatives

Abstract

The synthesis and structure-activity relationships of a homologous series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium(III) complexes bearing thiol-terminated alkyl sidechains from three to nine carbons in length are reported. The observed binding with human serum albumin (HSA) of the compounds having C-3 through C-7 sidechain lengths was inhibited by homocysteine in a manner consistent with single-site binding. The observed binding with HSA of the compounds having C-8 and C-9 sidechain lengths was only partly inhibited by homocysteine, consistent with multi-site binding. The binding affinity of the C-7 compound could be related to the HSA oxidation state. 2D 1H–1H NMR TOCSY provided evidence of covalent binding of the europium analog of the C-6 compound to HSA-Cys34. The longitudinal water-proton MRI relaxivities of the gadolinium complexes at 7 Tesla increased upon binding to HSA. Based on these results, the C-6 and C-7 compounds were identified as promising redox-sensitive MRI contrast agents.

Spectrophotometric determination and removal of unchelated europium ions from solutions containing Eu-diethylenetriaminepentaacetic acid chelate–peptide conjugates

“…A previously reported Gd-DOTA chelate that had been purified by normal phase column chromatography [16] was used as a negative control to validate our assay protocol. Using the xylenol orange spectrophotometric assay for determination of unchelated Eu ion concentration described in the Experimental Section, the control Gd-DOTA chelate did not exhibit a detectable level of unchelated Gd ions (i.e., no increase in absorbance at 573 compared to the reagent blank).…”

Improved Synthesis of 10-(2-Alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic Acid Derivatives Bearing Acid-Sensitive Linkers

“…Treatment of 10 19 and 11 21 with bromoacetyl bromide in DCM in the presence of 1N NaOH gave 12 and 13 in 92% and 94% yields, respectively (Scheme 2). 35 While it was previously reported that alkylations of the hydrobromide salt of 6 gave poor yields, even in presence of K 2 CO 3 , 26 we found that treatment of the hydrobromide salt 7 with K 2 CO 3 in acetonitrile for one hour at 70 °C prior to the addition of bromoacetamide 12 , followed by reaction at this temperature for one hour, produced 14 in 84% yield (Scheme 2).…”

“…Overall, the three-step reaction sequences starting from cyclen ( 9 ) produced DOTA monoamides 4 and 5 in 57–69% yields based on cyclen, about three-fold higher yields than the literature syntheses of these same compounds. 19,21 Thus, hydrobromide salts 7 and 8 can be used as alternatives to 6 in the preparation of sets of DOTA monoamides, avoiding the synthesis and characterization of intermediates that would result from monoalkylation of 9 followed by incorporation of three acetate arms, or of single DOTA monoamide targets on large scales, and will be especially useful in cases where the DOTA monoamide derivatives contain acid sensitive moieties.…”

“…20 We also synthesized Gd-DOTA monoamide complex 3 bearing an ω-thioheptyl side chain that showed higher binding affinity for HSA as compared to 2 . 21 DOTA monoamides 4 and 5 , intermediates in the published syntheses 19,21 of complexes 2 and 3 , respectively, were prepared by mono-activation of 1 with isobutyl chloroformate, followed by reaction with 6-tritylthiohexylamine and 7-tritylthioheptylamine, respectively, in good yields based on the amine starting materials. However, based on DOTA, the yields of 4 and 5 were 27% and 23%, respectively.…”

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“…[27] A clear explanation can be found for estimating the M: L ratios by the method of the known molecular percentage in analytical chemistry, [28,29] where the ratio of M: L to the complex formed between the metallic ions interacting with oxalic acid was found to be 1:2 or 1:3 from M: L ratios, which sets the metal ions to move to the formation of more stable complexes with ligand 18-crown-6-ether which are deposited more stable. [30,31] Clearly, the KSP (Constant solubility) values measured for the complex formed between metallic ions with oxalic acid are much lower than the KSP values of the complex formed between the metal ions with 18-crown-6-ether. [32,33] In the acidic media at pH 3, the OH groups in the acid are released to release molecules of water, thus creating the electronic couplings on the oxygen atoms of the hydroxyl group in the acid to bind with the metal ions in the lanthanides and the ions of the transition elements.…”