Caged [(18)F]FDG glycosylamines for imaging acidic tumor microenvironments using positron emission tomography Journal Article
| Authors: | Flavell, R. R.; Truillet, C.; Regan, M. K.; Ganguly, T.; Blecha, J. E.; Kurhanewicz, J.; Vanbrocklin, H. F.; Keshari, K. R.; Chang, C. J.; Evans, M. J.; Wilson, D. M. |
| Article 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 [18F]FDG amines. [18F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[18F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [18F]FDG amines is tunable in a systematic fashion, tracking the pKa of the parent amine. In vivo, a 4-phenylbenzylamine [18F]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. © 2015 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; positron emission tomography; mouse; gene overexpression; animal experiment; animal model; ph; in vivo study; drug structure; in vitro study; molecular imaging; drug synthesis; enzyme phosphorylation; carbonate dehydratase ix; drug accumulation; drug distribution; drug mechanism; drug uptake; fluorodeoxyglucose f 18; drug clearance; benign tumor; tracer; drug half life; drug conjugation; drug stability; acidity; reaction time; tumor microenvironment; drug purification; glucose transporter; cytochalasin b; bicarbonate; hexokinase; alkalinization; human; male; article; drug decomposition; pet-ct scanner; drug hydrolysis; prostate cancer cell line; hydrazone derivative; fluorodeoxyglycosylamine f 18; fluorodeoxyglycosyloxime f 18 |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 27 |
| Issue: | 1 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2016-01-20 |
| Start Page: | 170 |
| End Page: | 178 |
| Language: | English |
| DOI: | 10.1021/acs.bioconjchem.5b00584 |
| PROVIDER: | scopus |
| PUBMED: | 26649808 |
| PMCID: | PMC4854293 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 March 2016 -- Source: Scopus |
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