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

摘要

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 (C max ) was 31.60?±?0.15%ID/gram after 60?minutes (t max ). 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 (t 1/2 ) 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.