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

Abstract

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 Tc. The in vivo biodistribution of 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 Tc-EMIHPBP was investigated and showed that maximum concentration in bone (C ) was 31.60 ± 0.15%ID/gram after 60 minutes (t ). Cumulative residence of Tc-EMIHPBP in the bone [AUC (%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 Tc-EMIHPBP formulation to be eliminated from bone (t ) 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.

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“…All organs and tissues were separated, washed using normal saline and weighed. Samples from muscle, blood, and bone were collected and taken as 40%, 7%, and 10% of the total body weight, respectively . The radioactivity of each organ was measured in a NaI (Tl) γ‐counter.…”

Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer

“…Therefore, the results revealed methotrexate-alendronate conjugate as a potential therapeutic for the treatment of rheumatoid arthritis and osteoporosis by targeting osteoclastogenesis [35]. Motaleb et al synthesized and characterized a novel zoledronate conjugate, 22, and successfully radiolabeled with 99mTc [36]. Compound 22 displayed excellent biological activities with high preferential uptake to the bone with clearance from blood, soft tissues; and these results suggest that zoledronate conjugates is a promising drug as an anti-osteoporotic agent [36].…”

“…Motaleb et al synthesized and characterized a novel zoledronate conjugate, 22, and successfully radiolabeled with 99mTc [36]. Compound 22 displayed excellent biological activities with high preferential uptake to the bone with clearance from blood, soft tissues; and these results suggest that zoledronate conjugates is a promising drug as an anti-osteoporotic agent [36].…”