Caged [18F]-FDG Glycosylamines for Imaging Acidic Tumor Microenvironments

Presenting Author Senior Author
Name: Robert Flavell Name: David Wilson
Email: Email:
Presenting Author’s RIG/SRG: Nuclear Medicine  
Presenting Author's Lab Location: China Basin   

Abstract Information
Imaging Modality: PET/SPECT
Disease Application: Prostate Cancer
Complete author list: Robert R. Flavell, Charles Truillet, Melanie K. Regan, Tanushree Ganguly, Joseph E. Blecha, John Kurhanewicz, Henry F. VanBrocklin, Kayvan R. Keshari, Christopher J. Chang, Michael J. Evans, David M. Wilson
Abstract highlights: Acidic interstitial pH is a promising biomarker for detecting aggressive cancer subtypes. We present a new method of imaging interstitial pH based on 18F-FDG amines, which are prodrug derivatives of 18F-FDG, the commonly used oncologic PET imaging tracer. The compounds were validated in murine models of prostate cancer.
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. Thus, interstitial acidity is a promising biomarker for the detection of aggressive cancer subtypes. Here, we present a new class of positron emission tomography (PET) imaging tracers, termed 18F-FDG amines, designed to image acidic interstitial pH.
18F-FDG amines and a control 18F-FDG oxime compound were synthesized in one step from 18F-FDG. Acid-dependent decomposition to 18F-FDG was evaluated in solution using HPLC and in PC3 cells. PET imaging and biodistribution studies were performed in PC3 xenograft mice.
18F-FDG amines operate via a two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[18F]-fluoro-D-glucose (FDG), which is subsequently accumulated by glucose avid cells. In contrast, the negative control compound 18F-FDG oxime, structurally homologous to the 18F-FDG amines, does not decompose to form FDG. 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. In contrast, the control 18F-FDG oxime could not be decomposed to 18F-FDG under acidic conditions, and had very low uptake in tumor. Uptake of FDG amines in the xenograft could be attenuated upon treatment with sodium bicarbonate, which is known to alkalinize tumors. Similarly, uptake of FDG amines was reduced in the PC3-CAIX xenograft model, which is genetically modified to overexpress carbonic anhydrase, causing an increase in tumoral pH.
18F-FDG glycosylamines represent a viable approach for imaging acidic interstitial pH with potential for clinical translation.