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Synthesis, Biological Evaluation and Molecular Docking Studies of High‐Affinity Bone Targeting N,N ' ‐Bis (alendronate) Diethylenetriamene‐ N,N' ‐Triacetic Acid: A Bifunctional Bone Scintigraphy Agent
Author(s) -
Chadha Nidhi,
Sinha Deepa,
Tiwari Anjani K.,
Chuttani Krishna,
Mishra Anil K.
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12194
Subject(s) - bisphosphonate , biodistribution , farnesyl diphosphate synthase , chemistry , hydroxyapatites , conjugate , geranylgeranyl pyrophosphate , osteocalcin , diphosphonates , alkaline phosphatase , biochemistry , osteoporosis , calcium , in vitro , enzyme , bone resorption , biosynthesis , medicine , prenylation , mathematical analysis , mathematics , organic chemistry
A bisphosphonate derivative DTPA ‐bis(alendronate) conjugate has been synthesized and evaluated as potential radiopharmaceutical for bone imaging. The compound was synthesized by the covalent coupling of DTPA ‐bis(anhydride) with alendronate and was char‐acterized on the basis of IR , NMR and mass spectroscopy. It was labelled with 99m Tc with 96% efficacy and was found stable for about 24 h under physiological conditions. Blood kinetic studies of 99m Tc DTPA ‐bis(alendronate) showed a biexponential pattern as well as quick washout from the blood circulation. The biological t 1/2 (F) and t 1/2 (S) were found to be 50 min ± 0.001 and 6 h 30 min ± 0.005, respectively. Imaging and biodistribution studies showed a significant accumulation of 99m Tc DTPA ‐bis(alendronate) conjugate at bone site. Bone‐to‐muscles ratios were 12.08 ± 0.001 at 1 h, 45.33 ± 0.001 at 4 h and 35.83 ± 0.001 at 24 h after post‐injection, respectively. The receptor binding of the 99m Tc‐ DTPA ‐bis (alendronate) was established on human bone cell line (Soas‐2) revealed K D = 0.86 n m . The preliminary result of the 99m Tc‐ DTPA ‐bis(alendronate) is encouraging to carrying out further in vivo experiment for targeted bone imaging because of good‐bone‐to‐normal‐organ contrast. Further docking analysis with molecular targets, farnesyl diphosphate synthase, geranylgeranyl pyrophosphate and osteocalcin revealed the high affinity of −17.419 and thus represents strong potential of bone‐imaging agent.