Development and Pharmacological Evaluation of New Bone-Targeted 99mTc-Radiolabeled Bisphosphonates
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- 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-N-acetic acid, iminodiacetic acid, 3-((2-aminoethyl)thio)-3-(1H-imidazol-4-yl)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/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 in vitro 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.