title: Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography.
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.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Flavell
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Truillet
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Regan
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Ganguly
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Blecha
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: John
authors.initials: J
authors.lastname: Kurhanewicz
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.affiliation: Department of Radiology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Kayvan R
authors.initials: KR
authors.lastname: Keshari
authors.affiliation: Departments of Chemistry and Molecular and Cell Biology and the Howard Hughes Medical Institute, University of California , Berkeley, California 94720, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California , San Francisco, California 94158, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D010091:Oximes / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D011355:Prodrugs / Q000737:chemistry; D011854:Radiochemistry / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000588:Amines; D010091:Oximes; D011355:Prodrugs; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18