68 Ga labeled Erlotinib: A novel PET probe for imaging EGFR over-expressing tumors
| Autor: | Kumar Prabhash, Akanksha Jain, Mythili Kameswaran, Usha Pandey, Ashutosh Dash, Haladhar Dev Sarma |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Biodistribution Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry 03 medical and health sciences 0302 clinical medicine In vivo Drug Discovery medicine heterocyclic compounds neoplasms Molecular Biology Chemistry Organic Chemistry respiratory tract diseases Radioconjugate 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Molecular Medicine Erlotinib Molecular imaging A431 cells Tyrosine kinase medicine.drug Conjugate |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:4552-4557 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2017.08.065 |
| Popis: | Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with 68Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with 68Ga in 95±2% yield, as evidenced by HPLC characterization. The logP value of 68Ga-NOTA-Erlotinib was - (0.6±0.1). The 68Ga-NOTA-Erlotinib conjugate was characterized using its natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, 68Ga-NOTA-Erlotinib exhibited an uptake of 9.8±0.4% in A431 cells which was inhibited by 55.1±0.2% on addition of cold Erlotinib (10µg) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, 68Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5±0.1% ID/g at 30minp.i.; 0.7±0.2% ID/g at 1hp.i.). Hepatobiliary clearance of the radioconjugate was observed. The 68Ga-NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of 68Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a 68Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of 68Ga labeled TKI for imaging of EGFR over-expressing tumors. |
| Databáze: | OpenAIRE |
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