title: Development and Pharmacological Evaluation of New Bone-Targeted (99m)Tc-Radiolabeled Bisphosphonates.
abstract: 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/(99m)Tc(CO)3(κ(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 (99m)Tc tracers were stable in vitro and exhibited binding to hydroxyapatite. In biodistribution studies, all of the (99m)Tc complexes exhibited high bone uptake superior to that of 25, which is the directly (99m)Tc-labeled bisphosphonate 3, and comparable to that of (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). The tracers [(99m)Tc(CO)3(6)] (26), [(99m)Tc(CO)3(9)] (27), [(99m)Tc(CO)3(11)] (28), and [(99m)Tc(CO)3(15)] (29) exhibited higher bone/blood ratios than (99m)Tc-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.
authors.affiliation: Department of Pharmacy, School of Health Sciences, Frederick University , 1036 Nicosia, Cyprus.
authors.forename: George
authors.initials: G
authors.lastname: Makris
authors.forename: Eirini D
authors.initials: ED
authors.lastname: Tseligka
authors.affiliation: Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), NCSR "Demokritos" 15310 Agia Paraskevi-Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Pirmettis
authors.affiliation: Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), NCSR "Demokritos" 15310 Agia Paraskevi-Athens, Greece.
authors.forename: Minas S
authors.initials: MS
authors.lastname: Papadopoulos
authors.affiliation: Department of Life and Health Sciences, University of Nicosia , 1700 Nicosia, Cyprus.
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Vizirianakis
authors.forename: Dionysia
authors.initials: D
authors.lastname: Papagiannopoulou
mesh_terms: D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004164:Diphosphonates / Q000737:chemistry* / Q000378:metabolism; D017886:Durapatite / Q000737:chemistry; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D015609:Organotechnetium Compounds / Q000008:administration & dosage / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry; D013667:Technetium / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D004164:Diphosphonates; D008024:Ligands; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C027474:methylene diphosphonate; D012211:Rhenium; D013667:Technetium; D017886:Durapatite
keywords: bisphosphonates; cell studies; imaging agents; rhenium; technetium-99m