A Robust and Convergent Synthesis of Dipeptide−DOTAM Conjugates as Chelators for Lanthanide Ions:  New PARACEST MRI Agents

Abstract

A generally applicable synthetic approach to dipeptide-DOTAM conjugates has been developed which is based on the peralkylation of 1,4,7,10-tetraazacyclododecane (cyclen) with protected N-iodoacetyl dipeptides. Standardized procedures were used for the alkylation, metalation, and purification of the resultant lanthanide complexes. Using this approach, we have been able to rapidly and reliably prepare and screen five different ligands each with up to six lanthanide ions. This preliminary investigation has identified several paramagnetic compounds with strong chemical exchange saturation transfer (PARACEST) properties in water at physiological temperature and pH. Extension of the synthetic approach to a wide variety of amino acids is possible.

Optimized MRI contrast for on‐resonance proton exchange processes of PARACEST agents in biological systems

“…A PARACEST agent containing a Tm 3ϩ cation, cyclen ring, ϪCH 2 C(O)Ϫ linker, and the Gly-Lys dipeptide sequence as functionalized side chains (Tm 3ϩ -DOTAM-GlyLys) was synthesized as described previously (11). Briefly, DOTAM-Gly-Lys was synthesized by tetraalkylation of cyclen with the corresponding iodoacetyl dipeptide sequence (C-terminal ester).…”

“…Diamagnetic and paramagnetic chemical exchange saturation transfer (PARACEST) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) agents have many possible medical and biologic applications, including the measurement of tissue pH based on the pH dependence of the exchange rate of amide protons with bulk water protons (13)(14)(15), the measurement of tissue temperature using the linear dependence of the bound water chemical shift on temperature (16,17), enzymatic activity (18), and metabolite levels (19)(20)(21). The CEST detection sensitivity (or CEST effect) is defined as the change in the bulk water signal intensity of the agent solution following irradiation of the exchangeable protons.…”

Evaluating pH in the Extracellular Tumor Microenvironment Using CEST MRI and Other Imaging Methods

“…An alternative to ratiometric PARACEST is the use of linewidth analysis of a single CEST peak (Figure 17) [62, 63]. The linewidth of the CEST effect of Tm-DOTAM-Gly-Lys is independent of agent concentration for given saturation pulse conditions.…”

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

“…Derivatives bearing benzyl and/or additional carboxylic groups as albumin-binding agents [230] as well as the glycine derivative, DOTAM-Gly, have been synthesized through an appropriate bromoderivatives, primarily for applications of complexes of the ligands as PARACEST agents [231]. On the other hand, for synthesis of tetrakis(dipeptide)-DOTAMs, the reaction of cyclen with N-iodoacetyl-dipeptides in acetonitrile and in the presence of DIPEA was utilized [232]. A similar strategy was applied on synthesis of DOTAM-tetrakis(dipeptides) having different ester group(s) [233] (Scheme 3.43).…”