H4octapa: synthesis, solution equilibria and complexes with useful radiopharmaceutical metal ions

H4octapa is an extremely versatile acyclic chelator for a wide variety of medicinally relevant metal ions, forming complexes of both high thermodynamic and kinetic stability. This work reports a significantly simplified 3 step high yield straightforward synthesis of H4octapa directly from EDDA. Crystals of the octa-protonated form of the ligand [H8octapa]4+ as its tetrachloride salt, and of the mixed lanthanum–sodium salt of [La(octapa)]− were isolated and characterized by X-ray diffraction. All eight protonation constants for the ligand were determined through combined potentiometric–spectrophotometric titrations and in batch experiments using UV spectrophotometry and 1H NMR spectroscopy. Synthesis, characterisation and solution equilibria studies are presented for complexes [Ln(octapa)]− (Ln = lanthanide element) with Sm(III), Dy(III), and Yb(III) (each of which have radiopharmaceutical applications). Complex formation equilibria studies provided evidence of Ln(Hoctapa), [Ln(octapa)]− and [Ln(octapa)(OH)]2− species in solution, and their stability constants were evaluated by pH-potentiometric competition titrations using [ttha]6− as a competing ligand, and by UV-vis spectrophotometric measurements. The high stability constants of the [Ln(octapa)]− complexes with Sm(III), Dy(III), and Yb(III) (log KSmL = 20.10(2), log KDyL = 20.14(3) and log KYbL = 19.90(1)) are similar to the published values for other lanthanides and consequently these initial investigations confirm H4octapa as a valuable ligand for Sm(III), Dy(III), Yb(III) and other Ln for application in diagnostic and therapeutic nuclear medicine.