Rapid Thermodynamically Stable Complex Formation of [^nat/111In]In³⁺, [^nat/90Y]Y³⁺, and [^nat/177Lu]Lu³⁺ with H₆dappa

Abstract

A phosphinate-bearing picolinic acid-based chelating ligand (H6dappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In3+, Lu3+, Y3+, Sc3+, La3+, Bi3+). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of H6dappa with four metal ions (In3+, Lu3+, Y3+, Sc3+) was deeply investigated via potentiometric and spectrophotometric (UV–vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand–ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([111In]­In3+, [177Lu]­Lu3+, [90Y]­Y3+), and the serum stability of [111In]­[In­(dappa)]3– was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that H6dappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/μmol and 28.2 GBq/μmol were achieved for [111In]­In3+ and [177Lu]­Lu3+, respectively. For H6dappa, high thermodynamic stability did not correlate with kinetic inertnesslability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.

Indium(III) in the “Periodic Table” of Di(2-pyridyl) Ketone: An Unprecedented Transformation of the Ligand and Solid-State 115In NMR Spectroscopy as a Valuable Structural Tool

“…perovskites), − MOF chemistry (e.g. as sensors), − medicinal chemistry (e.g., as radiopharmaceuticals), − heterogeneous (e.g. cycloaddition of CO 2 with epoxides) , and homogeneous (e.g.…”

Phosphonate Chelators for Medicinal Metal Ions

“…The strategy for the synthesis of H 6 phospa and H 6 dipedpa (Scheme ) was to build first the dipicolinate ethylenediamine scaffold through the synthesis of 1 (as reported elsewhere , ) and then to functionalize the resultant secondary amines to yield two distinct ligands, differing only in the length of the amine-phosphonate bridging unit. H 6 phospa was synthesized via a Kabachnik-Fields reaction, which forms a methylene bridge between the amine and phosphonate group following the dissolution and heating of 1 and phosphorous acid in hydrochloric acid (HCl; 6 M) and the slow addition of paraformaldehyde.…”

“…We recently reported the decadentate phosphinate-containing ligand H 6 dappa (Chart ), which can also be compared with H 6 phospa. The substitution of a carboxyethyl phosphinic acid for a phosphonic acid in H 6 phospa greatly increases the basicity of the N en atoms (from log K 1 = 7.96(1) and log K 2 = 5.48(2) to log K 1 = 11.43(1) and log K 2 = 10.05(1)) and the overall basicity over those two steps log β 2 (from 13.44(1) to 21.48(1)) due to the electronic differences between phosphonates and phosphinates, as well as the hydrogen bonding present in H 6 phospa.…”

“…No investigation of H 6 phospa thermodynamic parameters have been explored. Another more recent report is of the phosphinate-bearing picolinic acid derivative H 6 dappa . While a similar lability with [ 111 In]­In 3+ was reported, in-depth thermodynamic studies and density functional theory (DFT) calculations provide insight into the reason behind the complex’s low kinetic inertness and how to mitigate lability if desired.…”

Dual-Labelling Strategies for Nuclear and Fluorescence Molecular Imaging: Current Status and Future Perspectives

“…This ligand shows interesting fluorescence properties after the addition of metal ions and is thus a promising system for nuclear/optical imaging [114]. H 6 dappa is a phosphinate-bearing picolinic acid-based chelating ligand for binding the radiometal ions 111 In III and 177 Lu III that has additional carboxylic acid groups for simultaneous introduction of fluorescence labels and targeting vectors [115]. H 4 pypa is a nonadentate ligand suitable for stable binding of radiometal ions such as 111 In III and 177 Lu III [116], 44 Sc III [117] and 89 Zr IV [118].…”