Kinetic modeling of 3'-deoxy-3'-18F-fluorothymidine for quantitative cell proliferation imaging in subcutaneous tumor models in mice.
3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a thymidine analog that was developed for measuring tumor proliferation with PET. The aim of this study was to establish a kinetic modeling analysis method for quantitative (18)F-FLT PET studies in subcutaneous tumor models in mice.


METHODS
To explore the validity of an image-derived left ventricular input function, we measured equilibrium constants for plasma and whole blood and metabolite fractions in blood after (18)F-FLT injection. In parallel, dynamic (18)F-FLT PET scans were acquired in 24 mice with a small-animal dedicated PET scanner to compare arterial blood activities obtained by PET and blood sampling. We then investigated kinetic models for (18)F-FLT in human epithelial carcinoma (A431) and Lewis lung carcinoma tumor models in mice. Three-compartment models with reversible phosphorylation (k(4) not equal 0, 3C5P) and irreversible phosphorylation (k(4) = 0, 3C4P) and a 2-compartment model (2C3P) were examined. The Akaike information criterion and F statistics were used to select the best model for the dataset. Gjedde-Patlak graphic analysis was performed, and standardized uptake values in the last frame were calculated for comparison purposes. In addition, quantitative PET parameters were compared with Ki-67 immunostaining results.


RESULTS
(18)F-FLT equilibrated rapidly (within 30 s) between plasma and whole blood, and metabolite fractions were negligible during PET scans. A high correlation between arterial blood sampling and PET data was observed. For 120-min dynamic PET data, the 3C5P model best described tissue time-activity curves for tumor regions. The net influx of (18)F-FLT (K(FLT)) and k(3) obtained with this model showed reasonable intersubject variability and discrimination ability for tumor models with different proliferation properties. The K(FLT) obtained from the 60- or 90-min data correlated well with that obtained from the 120-min data as well as with the Ki-67 results.


CONCLUSIONS
The image-derived arterial input function was found to be feasible for kinetic modeling studies of (18)F-FLT PET in mice, and kinetic modeling analysis with an adequate compartment model provided reliable kinetic parameters for measuring tumor proliferation.
Kim
Su Jin
SJ
Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Korea.
Lee
Jae Sung
JS
Im
Ki Chum
KC
Kim
Seog-Young
SY
Park
Soo-Ah
SA
Lee
Seung Jin
SJ
Oh
Seung Jun
SJ
Lee
Dong Soo
DS
Moon
Dae Hyuk
DH
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003198:Computer Simulation; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D007700:Kinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008954:Models, Biological; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012867:Skin / Q000000981:diagnostic imaging* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*
D015224:Dideoxynucleosides; D019275:Radiopharmaceuticals; C002854:alovudine