Abstract
The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with 64Cu-ATSM and extract useful physiological parameters. Methods: Tumor-bearing mice underwent 90-min dynamic PET scans with 64Cu-ATSM and CT scans with contrast. Irreversible and reversible two-tissue compartment models were fitted to time activity curves (TACs) obtained from whole tumor volumes and compared using the Akaike information criterion (AIC). Based on voxel-wise pharmacokinetic analysis, parametric maps of model rate constants k1, k3 and Ki were generated and compared to 64Cu-ATSM uptake. Results: Based on the AIC, an irreversible two-tissue compartment model was selected for voxel-wise pharmacokinetic analysis. Of the extracted parameters, k1 (~perfusion) showed a strong correlation with early tracer uptake (mean spearman R = 0.88) 5 min post injection (pi). Moreover, positive relationships were found between late tracer uptake (90 min pi) and both k3 and the net influx rate constant, Ki (mean spearman R = 0.56 and R = 0.86; respectively). Conclusion: This study shows the feasibility to extract relevant parameters from voxel-wise pharmacokinetic analysis to be used for preclinical validation of 64Cu-ATSM as a hypoxia-specific PET tracer.
Highlights
Tumor hypoxia is a key factor in the development of aggressive and therapy-resistant tumors [1,2,3].Several techniques have been applied for the evaluation of intratumoral oxygen tension with the purpose of improving treatment responsiveness, and for possible use in individualized treatment planning
The majority of PET tracers used for imaging of hypoxia belongs to a group of compounds termed nitroimidazoles that are reduced and become trapped in hypoxic tissue [9,10,11]. [18F]Fluoromisonidazole (18F-FMISO) was the first nitroimidazole-based PET
The heterogeneous uptake pattern of 64Cu-ATSM was observed within intratumoral regions in all mice
Summary
Tumor hypoxia is a key factor in the development of aggressive and therapy-resistant tumors [1,2,3].Several techniques have been applied for the evaluation of intratumoral oxygen tension with the purpose of improving treatment responsiveness, and for possible use in individualized treatment planning. Invasive oxygen electrode measurements provide direct quantitative information of tumor oxygenation and are generally considered the gold standard for the detection of tumor hypoxia [4,5,6,7]. This method is technically demanding and depends on the accessibility of the tumor for probe insertions [8]. Slow blood clearance means that this tracer produces rather low tumor-to-background ratios; a problem that has only partly been solved with different second generation nitroimidazoles that have been developed and evaluated [15,16,17,18]
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