Synthesis, Complexation Properties, and Evaluation of New Aminodiphosphonic Acids as Vector Molecules for <sup>68</sup>Ga Radiopharmaceuticals
Alesya Ya. Maruk,
Valery V. Ragulin,
Iurii A. Mitrofanov,
Galina S. Tsebrikova,
Vitaly P. Solov’ev,
Alexandr S. Lunev,
Kristina A. Lunyova,
Olga E. Klementyeva,
Vladimir E. Baulin,
Galina E. Kodina,
Aslan Yu. Tsivadse
Affiliations
Alesya Ya. Maruk
Department of Radiation Medical Technologies, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya str. 46, 123182 Moscow, Russia
Valery V. Ragulin
Laboratory of Organophosphorus Сompounds, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severnyi proezd 1, 142432 Chernogolovka, Russia
Iurii A. Mitrofanov
Department of Radiation Medical Technologies, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya str. 46, 123182 Moscow, Russia
Galina S. Tsebrikova
Laborotary of Novel Physicochemical Problems, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninskii pr. 31/4, 119071 Moscow, Russia
Vitaly P. Solov’ev
Laborotary of Novel Physicochemical Problems, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninskii pr. 31/4, 119071 Moscow, Russia
Alexandr S. Lunev
Department of Radiation Medical Technologies, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya str. 46, 123182 Moscow, Russia
Kristina A. Lunyova
Department of Radiation Medical Technologies, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya str. 46, 123182 Moscow, Russia
Olga E. Klementyeva
Department of Radiation Medical Technologies, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya str. 46, 123182 Moscow, Russia
Vladimir E. Baulin
Laboratory of Organophosphorus Сompounds, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severnyi proezd 1, 142432 Chernogolovka, Russia
Galina E. Kodina
Department of Radiation Medical Technologies, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya str. 46, 123182 Moscow, Russia
Aslan Yu. Tsivadse
Laborotary of Novel Physicochemical Problems, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninskii pr. 31/4, 119071 Moscow, Russia
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.
