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

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 (logK_GaL = 31.92 ± 0.32) significantly exceeds stability constant of Ga³⁺ complex with 8 (logK_GaL = 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.