Development and Pharmacological Evaluation of New Bone Targeted Tc-99m-Radiolabeled Bisphosphonates

作者：Makris George; Tseligka Eirini D; Pirmettis Ioannis; Papadopoulos Minas S; Vizirianakis Ioannis S; Papagiannopoulou Dionysia^*

来源：Molecular Pharmaceutics, 2016, 13(7): 2301-2317.

DOI：10.1021/acs.molpharmaceut.6b00081

• bisphosphonates
• technetium-99m
• rhenium
• cell studies
• imaging agents

A novel bisphosphonate, 1-(3aminopropylamino)ethane-1,1-diyldiphosphonic acid (3), was coupled to the tridentate chelators di-2-picolylamine, 2picolylamine-N-acetic acid, iminodiacetic acid, 34(2aminoethyl)thio)-3-(1H-imidazol-4-y-propanoic acid, and 2((2-carboxyethyl)thio)-3-(1H-imidazol-4-yl)propanoic acid to form ligands 6, 9, 11, 15, and 19, respectively. Organometallic complexes of the general formula [Re/Tc-99m(CO)(3)(kappa(3)-L)] were synthesized, where L denotes ligand 6, 9, 11, 15, or 19. The rhenium complexes were prepared at the macroscopic level and characterized by spectroscopic methods. The technetium-99m organometallic complexes were synthesized in high yield and were identified by comparative reversed-phase HPLC with their Re analogues. The Tc-99m tracers were stable in vitro and exhibited binding to hydroxyapatite. In biodistribution studies, all of the Tc-99m complexes exhibited high bone uptake superior to that of 25, which is the directly Tc-99m-labeled bisphosphonate 3, and comparable to that of Tc-99m-methylene diphosphonate ((TcMDP)-Tc-99m). The tracers [Tc-99m(C0)3(6)] (26), [Tc-99m(C0)3(9)] (27), [Tc-99m(C0)3(11)] (28), and [Tc-99m(C0)3(15)] (29) exhibited higher bone/blood ratios than (99m)-MDP. 26 had the highest bone uptake at 1 h p.i. The new bisphosphonates showed no substantial growth inhibitory capacity in PC-3, Saos-2, and MCF-7 established cancer cell lines at low concentrations. Incubation of 26 with the same cancer cell lines indicated a rapid and saturated uptake. The promising properties of 26-29 indicate their potential for use as bone-imaging agents.

• 出版日期2016-7