Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside.
The study was performed to compare the (18)F-labeled nitroimidazole compound fluoroazomycin arabinoside ((18)F-FAZA) with the standard hypoxia tracer fluoromisonidazole ((18)F-FMISO) in detection of tumor tissue hypoxia and to verify the oxygenation dependency of (18)F-FAZA uptake.


METHODS
Biodistribution of (18)F-FAZA was studied at various time points in EMT6 tumor-bearing BALB/c mice and in AR42J and A431 tumor-bearing nude mice and compared with that of (18)F-FMISO. The presence of tumor tissue hypoxia was verified in 5 EMT6 and 5 AR42J tumors using an oxygen-sensing needle electrode system. To evaluate the oxygenation dependency of (18)F-FAZA uptake, using the Munich prototype animal PET scanner, 2 serial PET scans were performed in 13 A431 tumor-bearing nude mice breathing pure oxygen or room air on 1 d and then selecting the other oxygen breathing condition on the following day. In addition, digital autoradiography was performed with EMT6 tumor-bearing (18)F-FAZA-dosed, nude mice breathing either room air (n = 8) or carbogen (n = 9).


RESULTS
Tissue partial pressure of oxygen (Po(2)) electrode measurements revealed that tumor hypoxia was present under room air breathing in EMT6 (tissue Po(2) = 2.9 +/- 2.6) and AR42J tumors (tissue Po(2) = 0.4 +/- 0.2), which was significantly lower compared with that of reference tissue (tissue Po(2) = 25.8 +/- 6.7 and tissue Po(2) = 29.0 +/- 3.0 [mean +/- SD], respectively; P < 0.01). In all tumor models, (18)F-FAZA displayed significantly higher tumor-to-muscle and tumor-to-blood ratios compared with (18)F-FMISO, indicating a faster clearance of (18)F-FAZA from normal tissues. In AR42J tumors, (18)F-FAZA tumor-to-normal ratios were found to increase over time. Serial animal (18)F-FAZA PET studies showed that the tumor-to-background ratio was significantly higher in animals breathing room air compared with that of animals breathing pure oxygen (7.3 +/- 2.3 vs. 4.2 +/- 1.2, respectively; P < 0.001). Similarly, autoradiography showed significantly higher tumor-to-muscle ratios in mice breathing room air compared with those of animals breathing carbogen (5.3 +/- 0.8 vs. 2.2 +/- 0.8; respectively; P < 0.02).


CONCLUSIONS
(18)F-FAZA shows superior biokinetics and is, thus, a promising PET tracer for the visualization of tumor hypoxia. This study also verified a hypoxia-specific uptake mechanism for (18)F-FAZA in murine tumor models.
Piert
Morand
M
Nuclear Medicine Clinic, Technical University of Munich, Munich, Germany. mpiert@umich.edu
Machulla
Hans-Jürgen
HJ
Picchio
Maria
M
Reischl
Gerald
G
Ziegler
Sybille
S
Kumar
Piyush
P
Wester
Hans-Jürgen
HJ
Beck
Roswitha
R
McEwan
Alexander J B
AJ
Wiebe
Leonard I
LI
Schwaiger
Markus
M
D000818:Animals; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D005260:Female; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009593:Nitroimidazoles / Q000493:pharmacokinetics*; D009928:Organ Specificity; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution
D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; C498052:fluoroazomycin arabinoside; D008920:Misonidazole; D010100:Oxygen