Improved synthesis of DOTA tetraamide ligands for lanthanide(III) ions: A tool for increasing the repertoire of potential PARACEST contrast agents for MRI and/or fluorescent sensors

The synthesis of new DOTA tetraamide (DOTAMR₄) compounds is of great interest given their application in the formation of Ln(III) complexes as potential PARACEST contrast agents in MRI or fluorescent molecular probes. In this context amino acid and peptide DOTAMR₄ derivatives are particularly attractive since the amino-acid and/or peptide moiety can show responsive properties dependent on a given stimuli which might translate to changes in water exchange rates of the corresponding Ln(III) complex. Current synthesis of DOTAMR₄ derivatives is typically carried out by reacting haloacetamide intermediates with cyclen. However, this method fails to generate the tetra-substituted products when bulky substituents are present in the haloacetamide and in some cases this intermediate cannot be prepared by conventional acylation procedures limiting the number of DOTAMR₄ compounds available for study. As a solution to these limitations, an improved methodology for the synthesis of DOTAMR₄ by coupling DOTA to an appropriate amine containing reagent (i.e. protected amino-acids with the α-amino group free) is presented in this work. Several DOTAMR₄ derivatives which are difficult or impossible to prepare with the traditional methodologies were easily obtained starting with DOTA. A new protocol was derived using this methodology for the solution-phase synthesis of DOTA peptide derivatives. With this methodology, many other DOTAMR₄ peptide and non-peptide derivatives have been prepared in our laboratories with several of these new compounds showing interesting properties for molecular imaging.