A Novel Radiotracer to Image Glycogen Metabolism in Tumors by Positron Emission Tomography

Abstract

The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized, and exploited with 18F-2-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a non-invasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that 18F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine (18F-NFTG) annotates glycogenesis in cancer cells and tumors in vivo, measured by PET. Specificity of glycogen labeling was demonstrated by isolating 18F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1, which inhibited 18F-NFTG uptake, while oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We further show that the rate of glycogenesis is cell cycle-regulated, enhanced during the non-proliferative state of cancer cells. We demonstrate that glycogen levels, 18F-NFTG, but not 18F-FDG uptake, increase proportionally with cell density and G1/G0 arrest with potential application in the assessment of activation of oncogenic pathways related to glycogenesis and the detection of post treatment tumor quiescence.

Preclinical Evaluation of 3-18F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection

“…Inflammation was induced in an aseptic inflammation model, through intramuscular injection of turpentine oil (30 mL) into the right posterior thigh of the mice, as previously described (15). For the analysis of radiotracer stability and metabolism, radiolabeled metabolites from plasma and tissues were quantified using a semiautomated method adapted from Smith et al (16), fully described in the supplemental materials.…”

Multiplexed imaging for diagnosis and therapy

“…For instance, PET generally informs on tissue phenotypes or processes (such as receptor expression [11][12][13][14][15][16] , microenvironment 17,18 , metabolism 16,[19][20][21][22][23] or perfusion) with outstanding sensitivity, but it is hampered by low resolution, scarcity of anatomic detail and dosimetric stipulations 24 . In contrast, MR provides anatomic detail with exquisite resolution, but lacks the sensitivity offered by radionuclide imaging; specific aspects of individual modalities are indicated in Table 3 (refs 24-31 ).…”

Radiopharmaceuticals as probes to characterize tumour tissue

“…Several probes for this target have been developed. These include clinically approved IgG molecules (about 150 kDa) such as 89 Zr-trastuzumab [37,104], antibody fragments including 68 Ga-DOTA-HER2 F(ab')2-trastuzumab [105], and much smaller Affibodies (about 6.5 kDa) including 18 F-GE-226 for PET [106] and 111 In-ABY-025 for analogous single photon imaging [107]. The long time to achieve contrast (4-5 days) due to the slow pharmacokinetics of IgGs and a requirement for titrating the optimal dose of the tracer in drugnaive patients are limitations of the antibody approach.…”

“…Whether this phenotype is limited to this particular model of senescence or more broadly applicable remains to be seen. The laboratory of Aboagye recently reported a novel radioprobe for imaging glycogenesis described later [111]. The probe could also find utility in rationalizing the ability of cancer cells presenting with excessive oncoproteins, e.g.…”

“…T140 derivatives such as Ac-TZ14011, have high affinity in the low nanomolar region for CXCR4, as well as high specificity. Modification of Ac-TZ14011 with bifunctional chelate for incorporation of the SPECT isotope 111 In resulted in a decrease in affinity for CXCR4 of almost sixfold. Despite reduced affinity, tumour tissue was clearly visualized, although the extent of uptake in the liver and spleen rendered the tracer unattractive for clinical development [145].…”