Triamidetriamine Bearing Macrobicyclic and Macrotricyclic Ligands: Potential Applications in the Development of Copper-64 Radiopharmaceuticals

Abstract

A versatile and straightforward synthetic approach is described for the preparation of triamide bearing analogues of sarcophagine hexaazamacrobicyclic cage ligands without the need for a templating metal ion. Reaction of 1,1,1-<i>tris</i>(aminoethyl)­ethane (tame) with 3 equiv of 2-chloroacetyl chloride, yields the <i>tris</i>(α-chloroamide) synthetic intermediate <b>6</b>, which when treated with either 1,1,1-<i>tris</i>(aminoethyl)­ethane or 1,4,7-triazacyclononane furnished two novel triamidetriamine cryptand ligands (<b>7</b> and <b>8</b> respectively). The Co­(III) and Cu­(II) complexes of cryptand <b>7</b> were prepared; however, cryptand <b>8</b> could not be metalated. The cryptands and the Co­(III) complex <b>9</b> have been characterized by elemental analysis, ¹H and ¹³C NMR spectroscopy, and X-ray crystallography. These studies confirm that the Co­(III) complex <b>9</b> adopts an octahedral geometry with three facial deprotonated amido-donors and three facial amine donor groups. The Cu­(II) complex <b>10</b> was characterized by elemental analysis, single crystal X-ray crystallography, cyclic voltammetry, and UV–visible absorption spectroscopy. In contrast to the Co­(III) complex (<b>9</b>), the Cu­(II) center adopts a square planar coordination geometry, with two amine and two deprotonated amido donor groups. Compound <b>10</b> exhibited a quasi-reversible, one-electron oxidation, which is assigned to the Cu^2+/3+ redox couple. These cryptands represent interesting ligands for radiopharmaceutical applications, and <b>7</b> has been labeled with ⁶⁴Cu to give ⁶⁴Cu-<b>10</b>. This complex showed good stability when subjected to l-cysteine challenge whereas low levels of decomplexation were evident in the presence of l-histidine