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First published online February 20, 2008, 10.2967/jnumed.107.047092
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Journal of Nuclear Medicine Vol. 49 No. 3 422-429
© 2008 by Society of Nuclear Medicine
doi: 10.2967/jnumed.107.047092

Basic Science Investigation

Dynamic Small-Animal PET Imaging of Tumor Proliferation with 3'-Deoxy-3'-18F-Fluorothymidine in a Genetically Engineered Mouse Model of High-Grade Gliomas

Michelle S. Bradbury1, Dolores Hambardzumyan2, Pat B. Zanzonico3, Jazmin Schwartz3, Shangde Cai4, Eva M. Burnazi4, Valerie Longo5, Steven M. Larson1 and Eric C. Holland2,6

1 Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York; 2 Cancer Biology and Genetics, Sloan Kettering Institute for Cancer Research, New York, New York; 3 Department of Medical Physics, Sloan Kettering Institute for Cancer Research, New York, New York; 4 Cyclotron and Radiochemistry Core, Sloan Kettering Institute for Cancer Research, New York, New York; 5 Small-Animal Imaging Core Facility, Sloan Kettering Institute for Cancer Research, New York, New York; and 6 Neurosurgery Service, Sloan Kettering Institute for Cancer Research, New York, New York

Correspondence: For correspondence or reprints contact: Michelle S. Bradbury, MD, PhD, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave., S-121, New York, NY 10021. E-mail: bradburm{at}mskcc.org

3'-Deoxy-3'-18F-fluorothymidine (18F-FLT), a partially metabolized thymidine analog, has been used in preclinical and clinical settings for the diagnostic evaluation and therapeutic monitoring of tumor proliferation status. We investigated the use of 18F-FLT for detecting and characterizing genetically engineered mouse (GEM) high-grade gliomas and evaluating the pharmacokinetics in GEM gliomas and normal brain tissue. Our goal was to develop a robust and reproducible method of kinetic analysis for the quantitative evaluation of tumor proliferation. Methods: Dynamic 18F-FLT PET imaging was performed for 60 min in glioma-bearing mice (n = 10) and in non–tumor-bearing control mice (n = 4) by use of a dedicated small-animal PET scanner. A 3-compartment, 4-parameter model was used to characterize 18F-FLT kinetics in vivo. For compartmental analysis, the arterial input was measured by placing a region of interest over the left ventricular blood pool and was corrected for partial-volume averaging. The 18F-FLT "trapping" and tissue flux model parameters were correlated with measured uptake (percentage injected dose per gram [%ID/g]) values at 60 min. Results: 18F-FLT uptake values (%ID/g) at 1 h in brain tumors were significantly greater than those in control brains (mean ± SD: 4.33 ± 0.58 and 0.86 ± 0.22, respectively; P < 0.0004). Kinetic analyses of the measured time–activity curves yielded independent, robust estimates of tracer transport and metabolism, with compartmental model–derived time–activity data closely fitting the measured data. Except for tracer transport, statistically significant differences were found between the applicable model parameters for tumors and normal brains. The tracer retention rate constant strongly correlated with measured 18F-FLT uptake values (r = 0.85, P < 0.0025), whereas a more moderate correlation was found between net 18F-FLT flux and 18F-FLT uptake values (r = 0.61, P < 0.02). Conclusion: A clinically relevant mouse glioma model was characterized by both static and dynamic small-animal PET imaging of 18F-FLT uptake. Time–activity curves were kinetically modeled to distinguish early transport from a subsequent tracer retention phase. Estimated 18F-FLT rate constants correlated positively with %ID/g measurements. Dynamic evaluation of 18F-FLT uptake offers a promising approach for noninvasively assessing cellular proliferation in vivo and for quantitatively monitoring new antiproliferation therapies.

Key Words: 18F-FLT • proliferation • brain tumors

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.


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