Hypoxia positron emission tomography imaging: combining information on perfusion and tracer retention to improve hypoxia specificity

<b>Background:</b> Static positron emission tomography (PET) allows mapping of tumor hypoxia, but low resolution and slow tracer retention/clearance results in poor image contrast and the risk of missing areas where hypoxic cells and necrosis are intermixed. Fully dynamic PET may improve accuracy but scan protocols suitable for routine clinical use are warranted. A modeling study proposed that hypoxia specificity can be improved by a clinically feasible blood-flow normalization procedure that only requires a 10- to 15-min dynamic scan (perfusion), followed by a short late static scan, but experimental validation is desired. <b>Methods:</b> Tumor-bearing mice were administered pimonidazole (hypoxia marker) and the PET hypoxia-tracer ¹⁸F-azomycin arabinoside (FAZA) and scanned for 3h. Subsequently, the distributions of FAZA (autoradiography) and hypoxic cells (pimonidazole) were compared on tissue sections. PET images collected in 10-min time intervals between 60 and 90 min post-injection (PET_early), which mimics the image contrast seen in patients, were compared voxel-by-voxel to 3-h PET (PET_late). For comparison, PET_early was normalized to the perfusion peak area, deduced from the first 10 min of the scan (PET_perf), and the resulting parameter PET_early/PET_perf was compared with PET_late. <b>Results:</b> Tissue analysis revealed a near-perfect spatial match between FAZA signal and hypoxic cell density (pimonidazole) 3 h post-injection, regardless of the tumor type. Only a weak inverse or no correlation between PET_perf and PET_late was seen, and the correlation between PET_early/PET_perf and PET_late proved inferior to the correlation between PET_early and PET_late. <b>Conclusions:</b> Late PET scans in rodents, unlike patients, provide an accurate map of hypoxia against which earlier time-point scans can be compared. PET_early and PET_late correlated to a variable extent but the correlation was lowered by normalization to perfusion (PET_early/PET_perf). Our study challenges the validity/robustness of a perfusion normalization approach. This may reflect that the chaotic tumor vasculature uncouples microregional blood flow and oxygen extraction.