Analysis of [18F]FLT PET data
3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) is an analogue of thymidine that as a nucleoside is needed in DNA replication in proliferating cells. The transport of thymidine and [18F]FLT into cells is facilitated by equilibrative nucleoside transporters (ENTs) and sodium-dependent concentrative carriers. In tumour cells the ENTs, mainly ENT1, are dominant. Inside the cell, both thymidine and [18F]FLT can be phosphorylated by thymidine kinase TK-1, and the resulting negatively charged monophosphate cannot escape the cell. Thymidine phosphorylase can degrade thymidine, but not [18F]FLT. TK-1 activity is increased at the S phase of the cell cycle. Thymidine is phosphorylated further by TK-2 and TK-3 for incorporation into new DNA, but [18F]FLT remains in the cells as the monophosphate.
Thymidine has also been labelled with 11C, and that tracer is incorporated in DNA. However, [11C]thymidine is rapidly metabolized in vivo to various 11C-carrying compounds causing tissue uptake that is not related to the rate of DNA synthesis.
In healthy humans, high [18F]FLT uptake is seen in the bone marrow, reflecting the high cell proliferation, and in the liver, kidneys, and urine bladder, reflecting the metabolism and excretion. Activation and reduction in cell proliferation in the spleen and bone marrow has been assessed using [18F]FLT (Hayman et al., 2011; Leimgruber et al., 2014; Campbell et al., 2015; McGuire et al., 2016; Tsujikawa et al., 2019).
In humans, most of the plasma radioactivity is due to the intact [18F]FLT after even 1 h, but the fraction of metabolites (mainly glucuronides) must still be corrected for kinetic analysis, both for the input function and for its tissue uptake (Frings et al., 2004; Kenny et al., 2005). Metabolites in plasma affect also the plasma-to-blood ratio, which must be accounted for when using image-derived input or blood sampler.
In clinical PET, [18F]FLT are usually analyzed semiquantitatively using SUV or SUV ratios. While the tumour uptake of [18F]FLT is usually lower than that of [18F]FDG, the uptake in normal tissue is usually much lower, providing higher tumour-to-background ratios.
For kinetic analysis, irreversible 2-tissue compartmental model or Patlak plot can be used. In some cases, reversible models such as Logan plot or reversible 2-tissue compartmental model may be optimal (Kramer et al., 2017). Tissue uptake of label-carrying metabolites can be taken into account by using modified Patlak plot (Kenny et al., 2005).
Tissue uptake of [18F]FLT is dependent on the transport and phosphorylation, and possibly on perfusion. Physiologically, the activity of transporters and thymidine kinase are often correlated, and [18F]FLT uptake can therefore be used for assessing tumour cell proliferation in clinical studies. In brain gliomas [18F]FLT uptake is related to transport through the disrupted blood-brain barrier, and does not reflect the rate of phosphorylation (k3); neither does the transport rate constant K1 (Shinomiya et al., 2013a and 2013b). In patients with idiopathic pulmonary arterial hypertension, k3 is increased as compared to patients with non-pulmonary arterial hypertension; in addition, higher k3 reflects higher expression of TK-1 and ENT1, and hyper-proliferative vascular fibroblasts (Ashek et al., 2018).
Cysouw MCF, Kramer GM, Frings V, De Langen AJ, Wondergem MJ, Kenny LM, Aboagye EO, Kobe C, Wolf J, Hoekstra OS, Boellaard R. Baseline and longitudinal variability of normal tissue uptake values of [18F]-fluorothymidine-PET images. Nucl Med Biol. 2017; 51: 18-24. doi: 10.1016/j.nucmedbio.2017.05.002.
Direcks WGE, Lammertsma AA, Molthoff CFM. 3'-Deoxy-3'-Fluorothymidine as a Tracer of Proliferation in Positron Emission Tomography. In: Deoxynucleoside Analogs in Cancer Therapy. Humana Press, 2006, pp 441-462.
Lubberink M, Direcs W, Emmering J, van Tinteren H, Hoekstra OS, van der Hoeven JJ, Molthoff CFM, Lammertsma AA. Validity of simplified 3'-deoxy-3'-[18F]fluorothymidine uptake measures for monitoring response to chemotherapy in locally advanced breast cancer. Mol Imaging Biol. 2012; 14: 777-782. doi: 10.1007/s11307-012-0547-1.
Shields AF, Grierson JR, Kozawa SM, Zheng M. Development of labeled thymidine analogs for imaging tumor proliferation. Nucl Med Biol. 1996; 23: 17-22. doi: 10.1016/0969-8051(95)02005-5.
Shields AF, Grierson JR, Dohmen BM, Machulla H-J, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, Muzik O, Mangner TJ. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998; 4(11): 1334-1336. doi: 10.1038/3337.
Updated at: 2019-12-29
Created at: 2018-08-11
Written by: Vesa Oikonen