A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2-Induced Glycolytic Reprogramming in Glioblastoma.

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/µmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

Cerebrovascular reactivity measurements using simultaneous 15O-water PET and ASL MRI: Impacts of arterial transit time, labeling efficiency, and hematocrit.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain to meet changing physiological demands and can predict the risk of cerebrovascular diseases. CVR can be obtained by measuring the change in cerebral blood flow (CBF) during a brain stress test where CBF is altered by a vasodilator such as acetazolamide. Although the gold standard to quantify CBF is PET imaging, the procedure is invasive and inaccessible to most patients. Arterial spin labeling (ASL) is a non-invasive and quantitative MRI method to measure CBF, and a consensus guideline has been published for the clinical application of ASL. Despite single post labeling delay (PLD) pseudo-continuous ASL (PCASL) being the recommended ASL technique for CBF quantification, it is sensitive to variations to the arterial transit time (ATT) and labeling efficiency induced by the vasodilator in CVR studies. Multi-PLD ASL controls for the changes in ATT, and velocity selective ASL is in theory insensitive to both ATT and labeling efficiency. Here we investigate CVR using simultaneous 15O-water PET and ASL MRI data from 19 healthy subjects. CVR and CBF measured by the ASL techniques were compared using PET as the reference technique. The impacts of blood T1 and labeling efficiency on ASL were assessed using individual measurements of hematocrit and flow velocity data of the carotid and vertebral arteries measured using phase-contrast MRI. We found that multi-PLD PCASL is the ASL technique most consistent with PET for CVR quantification (group mean CVR of the whole brain = 42±19% and 40±18% respectively). Single-PLD ASL underestimated the CVR of the whole brain significantly by 15±10% compared with PET (p<0.01, paired t-test). Changes in ATT pre- and post-acetazolamide was the principal factor affecting ASL-based CVR quantification. Variations in labeling efficiency and blood T1 had negligible effects.

True ultra-low-dose amyloid PET/MRI enhanced with deep learning for clinical interpretation.

PURPOSE: While sampled or short-frame realizations have shown the potential power of deep learning to reduce radiation dose for PET images, evidence in true injected ultra-low-dose cases is lacking. Therefore, we evaluated deep learning enhancement using a significantly reduced injected radiotracer protocol for amyloid PET/MRI. METHODS: Eighteen participants underwent two separate 18F-florbetaben PET/MRI studies in which an ultra-low-dose (6.64 ± 3.57 MBq, 2.2 ± 1.3% of standard) or a standard-dose (300 ± 14 MBq) was injected. The PET counts from the standard-dose list-mode data were also undersampled to approximate an ultra-low-dose session. A pre-trained convolutional neural network was fine-tuned using MR images and either the injected or sampled ultra-low-dose PET as inputs. Image quality of the enhanced images was evaluated using three metrics (peak signal-to-noise ratio, structural similarity, and root mean square error), as well as the coefficient of variation (CV) for regional standard uptake value ratios (SUVRs). Mean cerebral uptake was correlated across image types to assess the validity of the sampled realizations. To judge clinical performance, four trained readers scored image quality on a five-point scale (using 15% non-inferiority limits for proportion of studies rated 3 or better) and classified cases into amyloid-positive and negative studies. RESULTS: The deep learning-enhanced PET images showed marked improvement on all quality metrics compared with the low-dose images as well as having generally similar regional CVs as the standard-dose. All enhanced images were non-inferior to their standard-dose counterparts. Accuracy for amyloid status was high (97.2% and 91.7% for images enhanced from injected and sampled ultra-low-dose data, respectively) which was similar to intra-reader reproducibility of standard-dose images (98.6%). CONCLUSION: Deep learning methods can synthesize diagnostic-quality PET images from ultra-low injected dose simultaneous PET/MRI data, demonstrating the general validity of sampled realizations and the potential to reduce dose significantly for amyloid imaging.