Enantiopure bifunctional chelators for copper radiopharmaceuticals - Does chirality matter in radiotracer design?

Ajay N. Singh, Marianna Dakanali, Guiyang Hao, Saleh Ramezani, Amit Kumar, Xiankai Sun

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Abstract

It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H 2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-64Cu-1, RR-64Cu-1, SS-64Cu-1, and RS-64Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-64Cu-1, RR-64Cu-1, SS-64Cu-1, and RS- 64Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac- 64Cu-1, RR-64Cu-1, SS-64Cu-1, and RS- 64Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.

Original languageEnglish (US)
Pages (from-to)308-315
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume80
DOIs
Publication statusPublished - Jun 10 2014

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Keywords

  • Bifunctional chelator (BFC)
  • Copper-64
  • Diagnosis
  • Imaging
  • Molecular imaging
  • Positron emission tomography
  • Prognosis

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology
  • Medicine(all)

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