| Zoledronic acid, one kind of the typical third generation bisphosphonates with an imidazole ring, has high affinity for bone mineral and labeled with 99Tcm can be used as bone imaging agents. In this study, three novel zoledronic acid derivatives were synthesized and labeled with 99Tcm, in order to investigate the feasibility of them used as new bone imaging agent.In this paper, three novel zoledronic acid derivatives, 1-hydroxy-3-(2-butyl-1H-imidazole -1-yl)propane-1,1-bisphosphonate (BIPrDP), 1-hydroxy-4-(2-butyl-1H-imidazole-1-yl)butane- 1,1-bisphosphonate (BIBDP) and 1-hydroxy-5-(2-butyl-1H-imidazole-1-yl)pentane-1,1- bisphosphonate (BIPeDP) were prepared from the starting material 2-butyl-1H-imidazole and 3-bromopropionic acid ethyl ester,4-bromobutyric acid ethyl ester and 5-bromovaleric acid ethyl ester by three steps of reactions: N-alkylation, ester hydrolysis and phosphoric acid acylation, respectively. The important intermediates and targets were identified by elemental analysis, IR, MS and 1H-NMR.The three novel zoledronic acid derivatives were labeled with radionuclide 99Tcm to prepare 99Tcm- BIPrDP,99Tcm- BIBDP and 99Tcm- BIPeDP. When the amount of diphosphonic acid ligand and SnC12·2H2O were 5 mg and 100μg respectively, pH value was 4～6 and the reaction time was 30 min at boiling temperature, the radiochemical purity (RCP) and radiolabeling yield (RLY) of the three radioactive drugs were greater than 95%, and the labeled complexes were stable at least up to 6 h in vitro. The kinetics of the labeling reaction between BIBrDP and 99TcmO4- was also studied. The results indicated that the preparative reaction of 99Tcm-BIPeDP was a pseudo-first order reaction. The reaction temperature has significantly influence in the procedure, the radiolabeling yield increases obviously as the temperature increases. And in order to put the radiochemical purity and radiolabeling yield of clinical requirement (>90%), the reaction temperature should be higher than 79.31℃.The partition coefficients, plasma protein binding ratios, biodistribution and pharmacokinetics studies in mice as well as SPECT bone imaging in rabbits of 99Tcm- BIPrDP,99Tcm- BIBDP and 99Tcm- BIPeDP were also investigated to evaluate their biological properties, and compared with 99Tcm-ZL,99Tcm-IPrDP and 99Tcm-BIDP. The partition coefficients (log P) for 99Tcm- BIPrDP,99Tcm- BIBDP and 99Tcm- BIPeDP were -2.396,-2.675,-2.479 at pH 7.0 and -2.242,-2.245,-2.252 at pH 7.4. The plasma protein binding rates of three drugs were 66.63%,61.01% and 66.33%. The maximum bone uptake of 99Tcm- BIPrDP,99Tcm- BIBDP and 99Tcm- BIPeDP were 19.2, 10.6 and 7.82 %ID/g, which were highly persistent, and the bone-to-muscle uptake ratios were 23.7,26.52 and 16.88. The clear bone images in rabbits were obtained at 1 hour after injection of the three drugs. The three radiopharmaceuticals all have high bone uptake, preferable selective bone uptake, low uptake and rapid clearance from blood and other soft organs, which made them desirable for further investigation as novel bone imaging agents. From the comparation with 99Tcm-ZL,99Tcm-IPrDP and 99Tcm-BIDP, we found that when the imidazol ring contained substituents, or the chain between imidazolyl and bisphosphonate group increased in the molecular structure, the biological properties of 99Tcm labeled zoledronic acid derivatives were obviously superior to 99Tcm-ZL with no substituent group. On the whole, the three designed novel 99Tcm labeled zoledronic acid derivatives are worthy of further investigation and could be used as bone imaging agents in future. |
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