Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas.
3'-Deoxy-3'-fluorothymidine (FLT), a thymidine analog, is under investigation for monitoring cellular proliferation in gliomas, a potential measure of disease progression and response to therapy. Uptake may result from retention in the biosynthetic pathway or leakage via the disrupted blood-tumor barrier. Visual analysis or static measures of 18F-FLT uptake are problematic as transport and retention cannot be distinguished.


METHODS
Twelve patients with primary brain tumors were imaged for 90 min of dynamic 18F-FLT PET with arterial blood sampling. Total blood activity was corrected for labeled metabolites to provide an FLT input function. A 2-tissue compartment, 4-rate-constant model was used to determine blood-to-tissue transport (K1) and metabolic flux (K(FLT)). Modeling results were compared with MR images of blood-brain barrier (BBB) breakdown revealed by gadolinium (Gd) contrast enhancement. Parametric image maps of K1 and K(FLT) were produced by a mixture analysis approach.


RESULTS
Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and K(FLT) (flux) could be estimated independently for sufficiently high K1 values. However, estimation of K(FLT) was less robust at low K1 values, particularly those close to normal brain. K1 was higher for MRI contrast-enhancing (CE) tumors (0.053 +/- 0.029 mL/g/min) than noncontrast-enhancing (NCE) tumors (0.005 +/- 0.002 mL/g/min; P < 0.02), and K(FLT) was higher for high-grade tumors (0.018 +/- 0.008 mL/g/min, n = 9) than low-grade tumors (0.003 +/- 0.003 mL/g/min, n = 3; P < 0.01). The flux in NCE tumors was indistinguishable from contralateral normal brain (0.002 +/- 0.001 mL/g/min). For CE tumors, K1 was higher than K(FLT). Parametric images matched region-of-interest estimates of transport and flux. However, no patient has 18F-FLT uptake outside of the volume of increased permeability defined by MRI T1+Gd enhancement.


CONCLUSIONS
Modeling analysis of 18F-FLT PET data yielded robust estimates of K1 and K(FLT) for enhancing tumors with sufficiently high K1 and provides a clearer understanding of the relationship between transport and retention of 18F-FLT in gliomas. In tumors that show breakdown of the BBB, transport dominates 18F-FLT uptake. Transport across the BBB and modest rates of 18F-FLT phosphorylation appear to limit the assessment of cellular proliferation using 18F-FLT to highly proliferative tumors with significant BBB breakdown.
Muzi
Mark
M
Department of Radiology, University of Washington, Seattle, Washington 98195-6004, USA. muzi@u.washington.edu
Spence
Alexander M
AM
O'Sullivan
Finbarr
F
Mankoff
David A
DA
Wells
Joanne M
JM
Grierson
John R
JR
Link
Jeanne M
JM
Krohn
Kenneth A
KA
D000328:Adult; D000368:Aged; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D005260:Female; D005682:Gadolinium; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*
D015224:Dideoxynucleosides; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D005682:Gadolinium; C002854:alovudine