Preparation And Structure-Activity Relationship Investigation On A Series Of Technetium-99m Labeled Zoledronic Acid Derivatives

Zoledronic acid and its derivatives have high affinity for bone mineral and labeled with ^99mTc can be used as bone imaging agents. In this study, a series of Zoledronic acid derivatives, 1-Hydroxy-2-(2-isopropyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic (i-PIDP), 1-Hydroxy-2-(2-butyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic (BIDP) and 1-Hydroxy-2-(2,4-dimethyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic (DMIDP) were synthesized and labeled with ^99mTc in the presence of stannous chloride. In order to investigate the structure-activity relationships (SAR) of these compounds, the bio-evaluation of ^99mTc-i-PIDP, ^99mTc-BIDP and ^99mTc-DMIDP were studied and compared with other reported ^99mTc-Zoledronic acid derivatives.The compounds and key intermediates were characterized by elemental analysis, IR, MS and 1HNMR techniques. Many effects were considered in the preparation of ^99mTc-labeled Zoledronic acid derivatives such as the amount of ligand, ^99mTcO4-, SnCl₂·2H₂O, pH value and the reaction time. Study on the reaction kinetics of preparation of ^99mTc-BIDP was also carried out. The biodistribution and pharmacokinetics studies in mice and SPECT bone scan in rabbits as well as plasma protein binding ratios and partition coefficients of ^99mTc-i-PIDP, ^99mTc-BIDP and ^99mTc-DMIDP were also studied to evaluate their feasibilities as novel bone imaging agents.Satisfactory results were obtained when the amount of ligand, Na^99mTcO4, SnCl2·2H2O, were 5 mg, 37 MBq, 100μg, respectively, the pH value was between 4 and 6, and the labeling reaction continued for 30 min at room temperature (25±1 oC). The labeled complex was stable at least up to 6 h in vitro. The results of the labeling reaction between BIDP and ^99mTc indicated that it was a first order reaction. And in order to make the radio labeling yield (RLY) and radiochemical purity (RCP) of ^99mTc-BIDP more than 90%, the temperature of the labeling reaction must be kept above 12 oC. High selective bone uptake and quick clearance in soft tissues were obtained from the animal studies of these three radiopharmaceuticals, which made them desirable for further investigation as novel bone imaging agents. From the comparation with ^99mTc-ZL and other ^99mTc-labeled Zoledronic acid derivatives, we got a conclusion that when the imidazol ring substituted with alkyl in the molecular structure, the bone uptake become much higher and clearance in soft tissues become much faster. Howerer, if the alkyl chain is long enough, i.e. ^99mTc-BIDP, the blood concentration become much higher than other ^99mTc-labeled-Zoledronic acid derivatives (^99mTc-MIDP,^99mTc-EIDP and ^99mTc-DMIDP), so the quality of bone image becomes poor. On the whole, these designed novel ^99mTc-labeled-Zoledronic acid derivatives are all fit for bone imaging agents.