Applications of PET imaging with the proliferation marker [18F]-FLT

Abstract

[18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease.

Figure 1

Structure of nucleosides used for imaging cellular proliferation. Thymidine can be labeled with ¹¹C at either the pyridine methyl position or the urea carbonyl.

Figure 2

Diagram of thymidine (A) and FLT (B) uptake and metabolism, including transport, phosphorylation by TK1, synthesis of thymidine from uridine by TS, and reaction with DNA polymerase. Thymidine, but not FLT, is a substrate for DNA polymerase. FLT is metabolized to its glucuronide in the liver and excreted by the kidney (C). After some cancer drugs treatments the glucuronosyl transferase reaction may be inhibited.

Figure 3

FLT imaging can discriminate between radionecrosis and true tumor recurrence in primary brain tumors if the flux rate constant, K_FLT, is measured. That ability does not exist for FLT SUV or for FDG SUV.