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J Med Chem. 2017 Oct 12;60(19):8201-8217. doi: 10.1021/acs.jmedchem.7b01108. Epub 2017 Sep 20.

Exploring Structural Parameters for Pretargeting Radioligand Optimization.

Author information

1
Department of Radiology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
2
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
3
Department of Chemistry, Hunter College of the City University of New York , New York, New York 10065, United States.
4
Ph.D. Program in Chemistry, Graduate Center of the City University of New York , New York, New York 10016, United States.
5
Departments of Radiology and Pharmacology, Weill Cornell Medical College , New York, New York 10065, United States.
6
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.

Abstract

Pretargeting offers a way to enhance target specificity while reducing off-target radiation dose to healthy tissue during payload delivery. We recently reported the development of an 18F-based pretargeting strategy predicated on the inverse electron demand Diels-Alder reaction as well as the use of this approach to visualize pancreatic tumor tissue in vivo as early as 1 h postinjection. Herein, we report a comprehensive structure: pharmacokinetic relationship study of a library of 25 novel radioligands that aims to identify radiotracers with optimal pharmacokinetic and dosimetric properties. This investigation revealed key relationships between molecular structure and in vivo behavior and produced two lead candidates exhibiting rapid tumor targeting with high target-to-background activity concentration ratios at early time points. We believe this knowledge to be of high value for the design and clinical translation of next-generation pretargeting agents for the diagnosis and treatment of disease.

PMID:
28857566
PMCID:
PMC6521719
DOI:
10.1021/acs.jmedchem.7b01108
[Indexed for MEDLINE]
Free PMC Article

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