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

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-tris(aminoethyl)­ethane (tame) with 3 equiv
of 2-chloroacetyl chloride, yields the tris(α-chloroamide)
synthetic intermediate 6, which when treated with either
1,1,1-tris(aminoethyl)­ethane or 1,4,7-triazacyclononane
furnished two novel triamidetriamine cryptand ligands (7 and 8 respectively). The Co­(III) and Cu­(II) complexes
of cryptand 7 were prepared; however, cryptand 8 could not be metalated. The cryptands and the Co­(III) complex 9 have been characterized by elemental analysis, 1H and 13C NMR spectroscopy, and X-ray crystallography.
These studies confirm that the Co­(III) complex 9 adopts
an octahedral geometry with three facial deprotonated amido-donors
and three facial amine donor groups. The Cu­(II) complex 10 was characterized by elemental analysis, single crystal X-ray crystallography,
cyclic voltammetry, and UV–visible absorption spectroscopy.
In contrast to the Co­(III) complex (9), the Cu­(II) center
adopts a square planar coordination geometry, with two amine and two
deprotonated amido donor groups. Compound 10 exhibited
a quasi-reversible, one-electron oxidation, which is assigned to the
Cu2+/3+ redox couple. These cryptands represent interesting
ligands for radiopharmaceutical applications, and 7 has
been labeled with 64Cu to give 64Cu-10. This complex showed good stability when subjected to l-cysteine challenge whereas low levels of decomplexation were evident
in the presence of l-histidine.