Development and Pharmacological Evaluation of New Bone-Targeted 99mTc-Radiolabeled Bisphosphonates
详细信息 查看全文
- 作者：George Makris ; Eirini D. Tseligka ; Ioannis Pirmettis ; Minas S. Papadopoulos ; Ioannis S. Vizirianakis ; Dionysia Papagiannopoulou
- 刊名：Molecular Pharmaceutics
- 出版年：2016
- 出版时间：July 5, 2016
- 年：2016
- 卷：13
- 期：7
- 页码：2301-2317
- 全文大小：764K
- 年卷期：0
- ISSN：1543-8392
文摘
A novel bisphosphonate, 1-(3-aminopropylamino)ethane-1,1-diyldiphosphonic acid (3), was coupled to the tridentate chelators di-2-picolylamine, 2-picolylamine-<i>Ni>-acetic acid, iminodiacetic acid, 3-((2-aminoethyl)thio)-3-(1<i>Hi>-imidazol-4-yl)propanoic acid, and 2-((2-carboxyethyl)thio)-3-(1<i>Hi>-imidazol-4-yl)propanoic acid to form ligands 6, 9, 11, 15, and 19, respectively. Organometallic complexes of the general formula [Re/99mTc(CO)3(κ3-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 99mTc tracers were stable <i>in vitroi> and exhibited binding to hydroxyapatite. In biodistribution studies, all of the 99mTc complexes exhibited high bone uptake superior to that of 25, which is the directly 99mTc-labeled bisphosphonate 3, and comparable to that of 99mTc-methylene diphosphonate (99mTc-MDP). The tracers [99mTc(CO)3(6)] (26), [99mTc(CO)3(9)] (27), [99mTc(CO)3(11)] (28), and [99mTc(CO)3(15)] (29) exhibited higher bone/blood ratios than 99mTc-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.