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

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

View larger version (7K): [in this window] [in a new window]   FIGURE 1.  Three-compartment, 4-parameter model of 18F-FLT kinetics. 18F-FLT is transported from vascular space (1) into tissue, comprising exchangeable compartment (2) and metabolically trapped (i.e., phosphorylated) compartment (3). Four rate constants describe transfer among these compartments. CpFLT = concentration of 18F-FLT in arterial plasma; Ct,eFLT = concentration of 18F-FLT in exchangeable compartment; Ct,mFLT = concentration of phosphorylated (i.e., trapped) 18F-FLT.

View larger version (22K): [in this window] [in a new window]   FIGURE 2.  Transverse PET images of 18F-FLT uptake in non–tumor-bearing (control) (A) and tumor-bearing (B) mouse brains 60 min (i.e., 59–60 min) after intravenous injection. Intense accumulation of radiotracer was seen in GEM high-grade glioma model at level of maximum activity, with no appreciable intracranial uptake being seen in absence of tumor. Mean %ID/g values are indicated.

View larger version (14K): [in this window] [in a new window]   FIGURE 3.  Static and dynamic measurements of 18F-FLT uptake in tumor and control mice in terms of %ID/g (mean ± SD) (A), kinetic parameters (B), and correlations between %ID/g and retention rate constant, k3 (C), and metabolic flux, KFLT (D). Double asterisks in A indicate statistically significant difference in comparison with results for control mice (P < 0.0004). Asterisks in B indicate mean parameter values of less than 10–5 and therefore essentially zero. Significantly higher values for %ID/g and all parameters, except for K1, were observed in tumors compared with control mouse brains, and good correlations were observed between k3 or KFLT and %ID/g. Rate constants are expressed in mL/min/g; remaining rate constants are in units of min–1.

View larger version (30K): [in this window] [in a new window]   FIGURE 4.  Transverse 18F-FLT PET images (A–C) and fitted time–activity curves (D and E) corresponding to representative control (A, mouse 1) and tumor-bearing (C, mouse 10) mice. Tumor-bearing mice (B and C) were selected on basis of minimum (B) and maximum (C) mean %ID/g values for groups of mice studied; latter values were compared with mean %ID/g for control mouse (A). Corresponding time–activity data were kinetically analyzed by compartmental modeling (D and E); fitted time–activity data are represented by solid or dashed curves, and measured time–activity data are represented by data points.