Introducing fluorine-18 fluoromisonidazole positron emission tomography for the localisation and quantification of pig liver hypoxia

Abstract

Fluorine-18 labelled fluoromisonidazole ([18F]FMISO) has been shown to accumulate in hypoxic tissue in inverse proportion to tissue oxygenation. In order to evaluate the potential of [18F]FMISO as a possible positron emission tomography (PET) tracer for imaging of liver tissue hypoxia, we measured the [18F]FMISO uptake in 13 domestic pigs using dynamic PET scanning. Hypoxia was induced by segmental arterial hepatic occlusion. During the experimental procedure the fractional concentration of inspired oxygen (FiO2) was set to 0.67 in group A (n=6) and to 0.21 in group B (n=7) animals. Before and after arterial occlusion, the partial pressure of O2 in tissue (TPO2) and the arterial blood flow were determined in normal flow and flow-impaired liver segments. Standardised uptake values [SUV=kBq tissue (in g) / body weight (in kg) x injected dose (in kBq)] for [18F]FMISO were calculated from PET images obtained 3 hours after injection of about 10 MBq/kg body weight [18F]FMISO. Immediately before PET scanning, the mean arterial blood flow was significantly decreased in arterially occluded segments [group A: 0. 41 (0.32-0.52); group B: 0.24 (0.16-0.33) ml min-1 g-1] compared with normal flow segments [group A: 1.05 (0.76-1.46); group B: 1.14 (0.83-1.57) ml min-1 g-1; geometric mean (95% confidence limits); P<0.001 for both groups]. After PET scanning, the TPO2 of occluded segments (group A: 5.1 (4.1-6.4); group B: 3.5 (2.6-4.9) mmHg] was significantly decreased compared with normal flow segments [group A: 26.4 (21.2-33.0); group B: 18.2 (13.3-25.1) mmHg; P<0.001 for both groups]. During the 3-h PET scan, the mean [18F]FMISO SUV determined in occluded segments increased significantly to 3.84 (3.12-4.72) in group A and 5.7 (4.71-6.9) in group B, while the SUV remained unchanged in corresponding normal liver tissue [group A: 1.4 (1.14-1. 71); group B: 1.31 (1.09-1.57); P<0.001 for both groups]. Regardless of ventilation conditions, a significant inverse exponential relationship was found between the TPO2 and the [18F]FMISO SUV (r2=0. 88, P<0.001). Our results suggest that because tracer delivery to hypoxic tissues was maintained by the portal circulation, the [18F]FMISO accumulation in the liver was found to be directly related to the severity of tissue hypoxia. Thus, [18F]FMISO PET allows in vivo quantification of pig liver hypoxia using simple SUV analysis as long as tracer delivery is not critically reduced.

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

“…Bentzen et al (2002) found no correlation between [ 18 F]FMISO-PET and pO 2 electrode measurements in C3H mammary carcinomas. Piert et al (1999Piert et al ( , 2000 showed a correlation between [ 18 F]FMISO-PET data and pO 2 electrode measurements in a study of hypoxia in pig liver tissue. Until today, however, the potential of this PET technique still needs confirmation by appropriate procedures, such as comparative evaluation with nitroimidazolerelated assays.…”

Assessment of Hypoxia in Experimental Mice Tumours by [ 18 F] Fluoromisonidazole PET and pO 2 Electrode Measurements

“…3 and 4). In the work by Piert et al (26,40), it was found that, regardless of ventilation conditions, a signicant inverse relationship existed between mean pO 2 measurements by the Eppendorf electrode and the standardized uptake value of [ 18 F ]F M ISO evaluated by PET examination in liver tissue. The authors concluded that [ 18 F ]F M ISO PET allowed for in vivo quanti cation of pig liver hypoxia.…”

“…R aleigh et al (23) found that binding of pimonidazole in experimental mice tumours (as determined by immunohistochemistry) correlated well with pO 2 measurements, whereas this was not the case in two recent studies (24,25) using the 2-nitroimidazole EF 5 in rodent tumours and human squamous cell carcinomas, respectively. In the study by Piert et al (26) on hypoxia in the pig liver, a correlation between PET-assessed uptake of uoromisonidazole and Eppendo rf electrode measurements was shown, thus indicating that the binding of uoromisonidazole is directly related to the degree of hypoxia. In contrast, in the work by Kavanagh et al (27) no relationship was found between pO 2 measurements and the binding of misonidazole in murine tumours.…”

18F-fluoromisonidazole positron emission tomography can predict pathological necrosis of brain tumors

“…Oxygen distributions were assessed directly by Eppendorf pO 2 measurements. They concluded that the decrease in pO 2 was associated with an increase in the FMISO standardized uptake value (SUV) under pO 2 below 20 mmHg [10,11]. Bentzen et al examined mice with mammary carcinoma using FMISO and Eppendorf pO 2 measurement.…”