1. Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography.
- Author
-
Flavell, Robert R, Truillet, Charles, Regan, Melanie K, Ganguly, Tanushree, Blecha, Joseph E, Kurhanewicz, John, VanBrocklin, Henry F, Keshari, Kayvan R, Chang, Christopher J, Evans, Michael J, and Wilson, David M
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Nude ,Neoplasms ,Experimental ,Amines ,Oximes ,Fluorodeoxyglucose F18 ,Prodrugs ,Radiopharmaceuticals ,Positron-Emission Tomography ,Xenograft Model Antitumor Assays ,Hydrogen-Ion Concentration ,Radiochemistry ,Male ,Tumor Microenvironment ,Chemistry Techniques ,Synthetic ,Cancer ,Biomedical Imaging ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Biochemistry and Cell Biology - Abstract
Solid tumors are hypoxic with altered metabolism, resulting in secretion of acids into the extracellular matrix and lower relative pH, a feature associated with local invasion and metastasis. Therapeutic and diagnostic agents responsive to this microenvironment may improve tumor-specific delivery. Therefore, we pursued a general strategy whereby caged small-molecule drugs or imaging agents liberate their parent compounds in regions of low interstitial pH. In this manuscript, we present a new acid-labile prodrug method based on the glycosylamine linkage, and its application to a class of positron emission tomography (PET) imaging tracers, termed [(18)F]FDG amines. [(18)F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[(18)F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [(18)F]FDG amines is tunable in a systematic fashion, tracking the pKa of the parent amine. In vivo, a 4-phenylbenzylamine [(18)F]FDG amine congener showed greater relative accumulation in tumors over benign tissue, which could be attenuated upon tumor alkalinization using previously validated models, including sodium bicarbonate treatment, or overexpression of carbonic anhydrase. This new class of PET tracer represents a viable approach for imaging acidic interstitial pH with potential for clinical translation.
- Published
- 2016