Dynamic small-animal PET imaging of tumor proliferation with 3'-deoxy-3'-18F-fluorothymidine in a genetically engineered mouse model of high-grade gliomas.
3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-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 (18)F-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 (18)F-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 (18)F-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 (18)F-FLT "trapping" and tissue flux model parameters were correlated with measured uptake (percentage injected dose per gram [%ID/g]) values at 60 min.


RESULTS
(18)F-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 (18)F-FLT uptake values (r = 0.85, P < 0.0025), whereas a more moderate correlation was found between net (18)F-FLT flux and (18)F-FLT uptake values (r = 0.61, P < 0.02).


CONCLUSIONS
A clinically relevant mouse glioma model was characterized by both static and dynamic small-animal PET imaging of (18)F-FLT uptake. Time-activity curves were kinetically modeled to distinguish early transport from a subsequent tracer retention phase. Estimated (18)F-FLT rate constants correlated positively with %ID/g measurements. Dynamic evaluation of (18)F-FLT uptake offers a promising approach for noninvasively assessing cellular proliferation in vivo and for quantitatively monitoring new antiproliferation therapies.
Bradbury
Michelle S
MS
Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York 10021, USA. bradbum@mskcc.org
Hambardzumyan
Dolores
D
Zanzonico
Pat B
PB
Schwartz
Jazmin
J
Cai
Shangde
S
Burnazi
Eva M
EM
Longo
Valerie
V
Larson
Steven M
SM
Holland
Eric C
EC
D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution
D015224:Dideoxynucleosides; D007457:Iodine Radioisotopes; C002854:alovudine