Synthesis, Complexation Properties, and Evaluation of New Aminodiphosphonic Acids as Vector Molecules for 68Ga Radiopharmaceuticals

Abstract

Two new aminodiphosphonic acids derived from salicylic acid and its phosphonic analogue were prepared through a simple and efficient synthesis. 2-[(2-Amino-2,2-diphosphono)ethyloxy]-benzoic acid 8 and 2-[(2-amino-2,2-diphosphono)ethyloxy]-5-ethyl-phenylphosphonic acid 9 were evaluated for their applicability as 68Ga binding bone-seeking agents. Protonation constants of 8 and 9 and stability constants of the Ga3+ complexes with 8 and 9 in water were determined. The stability constant of Ga3+ complex with fully phosphorylated acid 9 (logKGaL = 31.92 ± 0.32) significantly exceeds stability constant of Ga3+ complex with 8 (logKGaL = 26.63 ± 0.24). Ligands 8 and 9 are as effective for Ga3+ cation binding as ethylenediamine-N,N’-diacetic-N,N’-bis(methy1enephosphonic) acid and ethylenediamine-N,N,N’,N’-tetrakis(methylenephosphonic) acid, respectively. The labelling process and stability of [68Ga]Ga-8 and [68Ga]Ga-9 were studied. Both 8 and 9 readily form 68Ga-complexes stable to ten-fold dilution with saline. However, in fetal bovine serum, only [68Ga]Ga-9 was stable enough to be subject to biological evaluation. It was injected into rats with bone pathology and aseptic inflammation of soft tissues. For [68Ga]Ga-9 in animals with a bone pathology model in 60 and 120 min after injection, a slight accumulation in the pathology site, stable blood percentage level, and moderate accumulation in the liver were observed. For animals with an aseptic inflammation, the accumulation of [68Ga]Ga-9 in the pathology site was higher than that in animals with bone pathology. Moreover, the accumulation of [68Ga]Ga-9 in inflammation sites was more stable than that for [68Ga]Ga-citrate. The percentage of [68Ga]Ga-9 in the blood decreased from 3.1% ID/g (60 min) to 1.5% ID/g (120 min). Accumulation in the liver was comparable to that obtained for [68Ga]Ga-citrate.

A Machine Learning-Based Study of Li+ and Na+ Metal Complexation with Phosphoryl-Containing Ligands for the Selective Extraction of Li+ from Brine

“…The present study attempted a computer-aided search for new phosphoryl-containing dipodandic ligands, characterized by high stability constant values for metal-ligand complexes with Li + in THF-CHCl 3 (4:1) with high Li + /Na + selectivity. These crownethers acyclic analogues have diverse applications as metallo-agents in biomedical applications [10] (e.g., radiopharmaceuticals and chemotherapeutic agents [11,12]), as extractants in separation processes [13][14][15], as compounds ion-selective membranes, and many other areas. The ligands considered here, involved in model development have been previously studied for complex formation with different metal cations in different solvents using various approaches [16][17][18][19][20][21].…”