Journal of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회지)

Korean Society of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회)
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Effect of PEG chain additive on 6,8-dichloro-2-phenylimidazo[1,2-a] pyridineacetamide (CB185) as a TSPO-binding ligand

  • Lee, Won Chang (Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National College of Medicine) ;
  • Lee, Sang Hee (Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National College of Medicine) ;
  • Denora, Nunzio (Department of Pharmacy - Pharmaceutical Sciences, University of Bari "A. Moro") ;
  • Laquintana, Valentino (Department of Pharmacy - Pharmaceutical Sciences, University of Bari "A. Moro") ;
  • Lee, Byung Chul (Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National College of Medicine) ;
  • Kim, Sang Eun (Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National College of Medicine)
  • Received : 2019.12.12
  • Accepted : 2019.12.28
  • Published : 2019.12.30
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Abstract

In our previous studies, we developed a 18F-labeled TSPO-binding ligand, named [18F]CB251, which has been proved to be a promising TSPO-binding PET radiotracer for the detection and monitoring of TSPO expression in pathological diseases. (Ki = 0.27 nM for TSPO, 1.96% ID/g of tumor uptake at 1h post-injection) Based on these results, we utilized 6,8-dichloro-2-phenylimidazo[1,2-a]pyridineacetamide analogs, CB185 (1) as a targeting moiety for the selective delivery of probes and anticancer molecules to TSPO-overexpressed tissues. In this study, we designed CB185 derivatives contains different PEG chains (n = 1, 3 and 5) and fluorescence dye (Cy5) to identify the necessary space between a TSPO-binding ligand and an anticancer agent. Three CB185 derivatives (11a-c) which contains Cy5 and PEG chain, were synthesized and the effect of PEG additive on their TSPO-binding affinities were evaluated using in vitro assays. The binding affinity for compounds 11a-c was lower than that of PK11195 (Ki = 3.2 nM), but still characterized by nanomolar binding affinity for TSPO (Ki = 46.5 nM for 11a, 51.0 nM for 11b, and 388.5 nM for 11c). These results showed that the conjugates are characterized by a moderate binding affinity toward TSPO except for compound 11c, which PEG chain consist of five PEG monomers. Our finding might add useful information to decide the appropriate PET chain length for developing new TSPO-targeting drug carriers.

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References

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