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. Conclusion: 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.