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

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 and 2-[(2-amino-2,2-diphosphono)ethyloxy]-5-ethyl-phenylphosphonic acid were evaluated for their applicability as Ga binding bone-seeking agents. Protonation constants of and and stability constants of the Ga complexes with and in water were determined. The stability constant of Ga complex with fully phosphorylated acid (log = 31.92 ± 0.32) significantly exceeds stability constant of Ga complex with (log = 26.63 ± 0.24). Ligands and are as effective for Ga cation binding as ethylenediamine- , -diacetic- , -bis(methy1enephosphonic) acid and ethylenediamine- , , , -tetrakis(methylenephosphonic) acid, respectively. The labelling process and stability of [ Ga]Ga- and [ Ga]Ga- were studied. Both and readily form Ga-complexes stable to ten-fold dilution with saline. However, in fetal bovine serum, only [ Ga]Ga- was stable enough to be subject to biological evaluation. It was injected into rats with bone pathology and aseptic inflammation of soft tissues. For [ Ga]Ga- 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 [ Ga]Ga- in the pathology site was higher than that in animals with bone pathology. Moreover, the accumulation of [ Ga]Ga- in inflammation sites was more stable than that for [ Ga]Ga-citrate. The percentage of [ Ga]Ga- 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 [ Ga]Ga-citrate.