ИСТИНА

Hypothesis: Folate receptors (FR) are cell membrane-associated target for nuclear medicine. FR are overexpressed by cells of various epithelial tumors, including tumors of the ovary, cervix, endometrium, lungs, kidneys, etc. Therefore, in nuclear medicine FR are very promising target for molecular imaging. The only healthy tissues with high FR expression are the kidneys [1]. (HE)n purification tag effectiveness for improvement of the biodistribution of 68Ga-radiopharmaceuticals was showed earlier using PSMA-based labeled compounds and affibodies [2]. In this study the influence of (HE)n tag introduction into folate-based molecule on the pharmacokinetics was evaluated. For this purpose two folic acid based compounds were synthesized and evaluated: NODAGA-1,4-buthanediamine‐folic acid (FA-I) and NODAGA-[Lys-(HE)2]‐folic acid (FA-II). FA-II contains (His-Glu)2 fragment in order to reduce kidneys accumulation. Methods: FA-I was synthesized according to the procedures described in the literature [1]. For synthesis of FA-II Fmoc protocols were used. All chemicals and solvents were of high-purity or pharmaceutical grade and were purchased from Sigma-Aldrich or Panreac. 68Ge/68Ga generator (Cyclotron Ltd, Russia) was used for the labeling of FA-I and FA-II with 68Ga. Radiochemical purity of labeled compounds was determined using radio-TLC and radio-HPLC. In vivo studies were carried out in normal laboratory animals, as well as in animals with xenografts of KB and HaLa cell lines. Results The procedure for 68Ga-labeling was developed (yield ≥ 95%). In in vivo experiments the accumulation of [68Ga]Ga-FA-II in healthy tissues reduced in comparison to [68Ga]Ga-FA-I, e.g. for kidneys the accumulation was 2-4 times lower. Tumor (KB) accumulation of [68Ga]Ga-FA-II remained the same as for [68Ga]Ga-FA-I. Conclusion: (HE)n tag introduction into folate-based radiopharmaceuticals is the promising approach to improve their pharmacokinetic properties.