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

Abstract

Hoctapa 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 Hoctapa directly from EDDA. Crystals of the octa-protonated form of the ligand [Hoctapa] 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 H 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)] species in solution, and their stability constants were evaluated by pH-potentiometric competition titrations using [ttha] 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 K = 20.10(2), log K = 20.14(3) and log K = 19.90(1)) are similar to the published values for other lanthanides and consequently these initial investigations confirm Hoctapa as a valuable ligand for Sm(iii), Dy(iii), Yb(iii) and other Ln for application in diagnostic and therapeutic nuclear medicine.

H4octox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry

“…The deprotonations of the neutral species M­(HL) may be attributed to the last protonated OH-quinoline moiety, based on the similarity of spectroscopic features to those of [Ga­(hox)] + and Ga­(oxine) 3 and on its higher basicity compared to that of the −COOH substituents. The last deprotonation is presumably a coordinated water molecule with higher p K a (10.41–10.81), as previously observed in similar systems. , …”

Influence of a Pre‐organized N‐Donor Group on the Coordination of Trivalent Actinides and Lanthanides by an Aminopolycarboxylate Complexant

“…The p K 7 value is also lower than the p K 8 value of DTPA and DTTA‐BuA (amide‐substituted DTPA) . This may indicate that the initial protonation occurs on the central amine, and is inhibited by the electron‐withdrawing influence of the picolinate group, as previously shown in the literature . Alternatively, the initial amine protonation may occur at the terminal iminodiacetate end, as implied by the results reported by Phukan et al .…”

“…Accordingly, no migration of the first proton associated with the central amine site of EDTA‐Mpic occurs, and the acidity of the second proton is increased. The third protonation equilibrium, p K 5 , occurs on the pyridine nitrogen, rendered more acidic by the electron‐withdrawing substituents . The two lowest acid dissociation constants, p K 4 and p K 3 , describe the protonation of the carboxylate sites.…”

Rigidified Derivative of the Non-macrocyclic Ligand H4OCTAPA for Stable Lanthanide(III) Complexation

“… a Data from ref ( 31 ) in 0.15 M NaCl unless otherwise indicated. b Data in 0.16 M NaCl from ref ( 29 ). c Data from ref ( 34 ).…”