A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers.
We compared the imaging characteristics and hypoxia selectivity of 4 hypoxia PET radiotracers ((18)F-fluoromisonidazole [(18)F-FMISO], (18)F-flortanidazole [(18)F-HX4], (18)F-fluoroazomycin arabinoside [(18)F-FAZA], and (64)Cu-diacetyl-bis(N4-methylsemicarbazone) [(64)Cu-ATSM]) in a single murine xenograft tumor model condition using small-animal PET imaging and combined ex vivo autoradiography and fluorescence immunohistochemistry.


METHODS
Nude mice bearing SQ20b xenograft tumors were administered 1 of 4 hypoxia PET tracers and images acquired 80-90 min after injection. Frozen sections from excised tumors were then evaluated for tracer distribution using digital autoradiography and compared with histologic markers of tumor hypoxia (pimonidazole, carbonic anydrase 9 [CA9]) and vascular perfusion (Hoechst 33342).


RESULTS
The highest tumor uptake was observed with (64)Cu-ATSM (maximum standardized uptake values [SUV(max)], 1.26 ± 0.13) and the lowest with (18)F-FAZA (SUVmax, 0.41 ± 0.24). (18)F-FMISO and (18)F-HX4 had similar intermediate tumor uptake (SUV(max), 0.76 ± 0.38 and 0.65 ± 0.19, respectively). Digital autoradiographs of hypoxia tracer distribution were compared pixel by pixel with images of immunohistochemistry stains. The fluorinated nitroimidazoles all showed radiotracer uptake increasing with pimonidazole and CA9 staining. (64)Cu-ATSM showed the opposite pattern, with highest radiotracer uptake observed in regions with the lowest pimonidazole and CA9 staining.


CONCLUSIONS
The fluorinated nitroimidazoles showed similar tumor distributions when compared with immunohistochemistry markers of hypoxia. Variations in tumor standardized uptake value and normal tissue distribution may determine the most appropriate clinical setting for each tracer. (64)Cu-ATSM showed the highest tumor accumulation and little renal clearance. However, the lack of correlation between (64)Cu-ATSM distribution and immunohistochemistry hypoxia markers casts some doubt on the hypoxia selectivity of (64)Cu-ATSM.
Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Sean
S
Carlin
Hanwen
H
Zhang
Megan
M
Reese
Nicholas N
NN
Ramos
Qing
Q
Chen
Sally-Ann
SA
Ricketts
D000818:Animals; D001345:Autoradiography; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D006801:Humans; D051379:Mice; D009593:Nitroimidazoles / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D013882:Thiosemicarbazones / Q000378:metabolism*
D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009593:Nitroimidazoles; D009942:Organometallic Compounds; D011849:Radioactive Tracers; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
PET; animal imaging; autoradiography; hypoxia; immunofluorescence