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Synthesis, preclinical, and pharmacokinetic evaluation of a new zoledronate derivative as a promising antiosteoporotic candidate using radiolabeling technique.

A novel zoledronic acid (ZL) derivative, 3-(2-ethyl-4-methyi-1H-imidazole-1-yl)-1-hydroxy-1-phosphonopropyl phosphonic acid (EMIHPBP), was synthesized, characterized, and successfully radiolabeled with 99m Tc. The in vivo biodistribution of 99m Tc-EMIHPBP was investigated and compared with the previously reported zoledronate derivatives aiming to formulate a novel zoledronate derivative with a high-potential uptake to bone as a promising antiosteoporotic candidate. To further evaluate the bone uptake efficiency, the pharmacokinetics of 99m Tc-EMIHPBP was investigated and showed that maximum concentration in bone (Cmax ) was 31.60 ± 0.15%ID/gram after 60 minutes (tmax ). Cumulative residence of 99m Tc-EMIHPBP in the bone [AUC (0-∞) (%ID∙min/gram bone)] was 3685.23, mean residence time was 384.354 minutes, and the calculated bone bioavailability was 15.831%. Finally, the time needed for half of the 99m Tc-EMIHPBP formulation to be eliminated from bone (t1/2 ) was 263.914 minutes. Excellent bone uptake can be obtained 1-hour postinjection with high bone/blood ratio of 23.76 detected with gamma counter. The biodistribution and kinetic studies could recommend EMIHPBP as a promising antiosteoporotic candidate with high selectivity to the skeletal system and rapid clearance from soft tissues.