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

Mechanism of Phosphorus-Carbon Bond Formation in the Amidoalkylation of Phosphonous Carboxylic Acids.

An unusual greater reactivity of phosphonous propionic acids was found in comparison with phosphonous propionic esters in carbamate version of Kabachnik-Fields reaction. Compounds of tricoordinated phosphorus generated in situ during the amidoalkylation of hydrophosphorylic compounds in acetyl chloride/acetic anhydride mixture were found by 31P NMR analysis. A hypothesis is proposed about the generation of spirophosphoranes in situ to explain the mechanism for the formation of the phosphorus-carbon bond in the reaction under study.