CS 
18F-3′-fluoro-3′-deoxythymidine
Author of the review:
It took a relatively long time before it was recognised that [18F]FDG is not an entirely ideal tracer for PET diagnostics as regards the response of malignant tumours to treatment. Chemotherapy causes strong inflammation in the tumour and the surrounding tissue, which significantly increases the local accumulation of [18F]FDG and thereby makes it very difficult to evaluate the progression or regression of the treated tumour.
18F-3′-fluoro-3′-deoxythymidine ([18F]FLT), a radioactively labelled form of a pyrimidine nucleoside, was chosen as a strong candidate for monitoring the response to therapy. [18F]FLT accumulates in proliferating cells as a marker of thymidine kinase activity, which increases up to 10-fold during cell division. The non-radioactive form of FLT was first described by the group of P. Langen in 1969 as a selective inhibitor of DNA synthesis. FLT labelled with radioactive 18F was first described by I. K. Wilson in 1991 as carrier-added [18F]FLT and in 1997 by J. R. Grierson as no-carrier-added [18F]FLT. In recent years, several further approaches have been published with the aim of increasing the radiochemical yield.
[18F]FLT was first used for PET imaging in 1998 by A. F. Shields, when a specific increase in activity was observed in proliferating tissues, including tumours and bone marrow, in animals and in patients with non-small-cell lung carcinoma.
Properties
[18F]FLT is a thymidine analogue containing the fluorine radionuclide 18F in position 3′. Fluorine 18F decays by positron emission (β+) with a half-life of 109.7 minutes. For diagnostic imaging by positron emission tomography (PET), the most important are the emitted γ photons with an energy of 511 keV, formed by the interaction of the emitted positrons with electrons (so-called positron annihilation). PET diagnostics using [18F]FLT is a very advantageous method for locating areas in tissues with increased cell proliferation.
Pharmacokinetics
After [18F]FLT passes through the cell membrane by carrier-facilitated transport or by passive diffusion, [18F]FLT undergoes phosphorylation catalysed by the cytosolic isoenzyme thymidine kinase-1 (TK1). In this monophosphorylated form it is retained in the cell; the substitution in the 3′ position prevents further incorporation into DNA. It follows that PET imaging in fact detects the enzyme activity of TK1. This assumption has recently also been supported by in vitro experiments on the human lung cancer cell line A549, in which a positive correlation was found between [18F]FLT uptake and TK1 enzyme activity, from which it follows that the uptake and accumulation of [18F]FLT very probably correspond to the degree of cell proliferation. In normal cells, TK1 gene expression is a strictly regulated process with a significant increase during DNA synthesis in the S phase of the cell cycle, but in malignantly transformed cells there is a large increase in expression, which is subsequently maintained permanently throughout the entire cell cycle. Because a several-fold increase in the rate of mitosis and cell proliferation is a typical feature of malignant tumour cells, [18F]FLT is one of the tumour-specific PET tracers.
Toxicity
The radiation dosimetry and toxicity determination of FLT was performed and published by the group of H. Vesselle. All doses used for intravenous administration of [18F]FLT are calculated on the basis of patient weight using 2.59 MBq/kg (0.07 mCi/kg) and with a maximum dose of 185 MBq (5 mCi). The distribution of [18F]FLT was found to be homogeneous in every organ. The whole-body dose and the doses for individual organs are lower than or comparable with other clinically used nuclear medicine techniques. At a minimum specific activity of 3.7 GBq/μmol (0.1 Ci/μmol), a single administration of labelled and unlabelled FLT corresponds to a mass of 12.2 μg, which is a dose about 3000× lower than the amount at which any first toxic effects (e.g. peripheral neuropathy) were recorded during the clinical use of FLT as part of antiretroviral therapy (AIDS treatment). A toxicological study of [18F]FLT at the single dose used for determining tumour cell proliferation and response to therapy showed no side effects on the body; there were no changes in the function of the liver, kidneys, or neurological functions of the brain. Among blood parameters there was a slight decrease in haematocrit, haemoglobin and erythrocytes, but the explanation is the increased hydration of patients by intravenous administration of physiological saline during the examination.
Use
Oncological applications
The importance of using [18F]FLT for tumour imaging lies, firstly, in determining tumour cell proliferation as a prognostic factor for a number of tumours, and further in detecting the reduced proliferative capacity of tumour cells responding to treatment. [18F]FLT PET imaging thus becomes particularly useful for evaluating tumour response to ongoing therapy.
Lung cancer
Several scientific studies have already shown that [18F]FLT uptake for PET imaging correlates with the rate of proliferation of human lung tumours. The importance of these findings lies particularly in the prognostic value of the tumour proliferation of non-small-cell lung carcinoma. [18F]FLT-PET imaging is evaluated for the detection of primary lung carcinoma, with relatively high accuracy even though the uptake of [18F]FLT by lung tumour cells is lower than the uptake of [18F]FDG. In studies that also include benign tumours, there is a significantly higher specificity for detecting malignancies using [18F]FLT-PET imaging compared with [18F]FLT-PET.
In assessing the involvement of regional lymph nodes by metastases, the specificity of [18F]FLT-PET was higher and the sensitivity slightly lower than [18F]FDG-PET. From these data it can be concluded that [18F]FDG-PET in combination with [18F]FLT-PET can improve the specificity for staging the disease and provide information on the growth rate of the tumour and its aggressiveness, which have a direct influence on prognosis and on the choice of appropriate treatment.
Brain tumours
Unlike [18F]FDG, [18F]FLT is able to cross the intact blood–brain barrier only slightly, and moreover normal brain tissue shows only a low degree of proliferation. For these reasons, [18F]FLT has a very low background in the brain on PET imaging. Uptake of [18F]FLT is, on the contrary, very significant in high-grade gliomas and other brain tumours associated with disruption of the blood–brain barrier. The result is a much more contrasted imaging of brain malignancies using [18F]FLT compared with [18F]FDG. Because of the limited passage of [18F]FLT across the intact blood–brain barrier, benign tumours and low-grade tumours cannot be detected in this way. Uptake of [18F]FLT correlates very well with the degree of tumour development, which makes it a good tool for the non-invasive determination of the degree of malignancy of brain tumours.
Lymphomas
Lymphomas show a much higher uptake of [18F]FLT into cells than other types of malignant tumours, probably also because of the high proportion of markedly proliferating cells in aggressive lymphomas. The overall uptake of [18F]FLT in lymphomas is comparable in magnitude with the uptake of [18F]FDG. Given the high uptake of [18F]FLT by normal bone marrow cells and the degree of bone marrow involvement in the development of lymphomas, the clinical use of [18F]FLT for staging this disease is still very limited. However, it has been found possible to use [18F]FLT-PET imaging to determine the response to chemotherapy in non-Hodgkin lymphomas and, if the lymphoma does not respond to treatment, to flexibly change the treatment regimen.
Breast cancer
In the case of breast cancer, [18F]FLT can be used to make an early estimate of the tumour's response to chemotherapeutic treatment. A decrease in [18F]FLT uptake during the first two weeks correlates much better with the values of the tumour marker CA27.29 and with tumour size on CT than [18F]FDG uptake, which makes [18F]FLT a better clinical indicator.
Although the uptake of [18F]FLT in primary breast cancer is lower than the uptake of [18F]FDG, the overall tumour-to-background contrast is comparable because of the low uptake of [18F]FLT in healthy tissue. [18F]FLT-PET can also successfully detect involvement of the axillary lymph nodes by metastases.
Cancer of the colon and rectum
Using [18F]FLT-PET imaging, not only colorectal carcinoma but also peritoneal and pulmonary metastases have been successfully detected. In the case of detecting liver metastases, a problem arises with high background activity caused by hepatic glucuronidation of [18F]FLT. Because the liver is a key site for the formation of colorectal carcinoma metastases, [18F]FLT cannot be reliably used for their detection. The potential of [18F]FLT therefore lies rather in evaluating the response of colorectal carcinoma to treatment in patients undergoing induction chemotherapy.
Head and neck cancer
The uptake of [18F]FLT by primary head and neck tumours is lower than the uptake of [18F]FDG; nevertheless, the reliability of detection using [18F]FLT is comparable with [18F]FDG. [18F]FLT-PET imaging successfully revealed metastases in the cervical lymph nodes, but increased uptake was also recorded in several benign lymph nodes. This phenomenon was caused by the high proliferation of B lymphocytes in the germinal centres of the lymph nodes.
Melanomas
[18F]FLT-PET imaging has demonstrated the ability to non-invasively determine the stage of involvement of regional lymph nodes. As in the case of breast cancer, [18F]FLT will probably not be able to completely replace the sensitivity of lymphoscintigraphy and resection of sentinel lymph nodes. Overall non-invasive staging of melanoma will probably also continue to remain the domain of [18F]FLT-PET/CT.
Soft tissue sarcomas
[18F]FLT-PET imaging is able to detect soft tissue sarcomas very sensitively and to identify further malignancies with significant clinical impact. The results of [18F]FLT uptake correlate with the mitotic index of tumour cells before treatment and can thus serve very well to predict the clinical response to treatment.
References
Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y: Basis of FLT as a cell proliferationmarker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 29(3):281-7, 2002. PubMed
Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, Luthra SK, Brady F, Price PM, Aboagye EO: 3′-deoxy-3′-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 63(13):3791-8, 2003. PubMed
Vesselle H, Grierson J, Peterson LM, Muzi M, Mankoff DA, Krohn KA: 18F-Fluorothymidine radiation dosimetry in human PET imaging studies. J Nucl Med 44(9):1482-8, 2003. PubMed
Turcotte E, Wiens LW, Grierson JR, Peterson LM, Wener MH, Vesselle H: Toxicology evaluation of radiotracerdoses of 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) for human PET imaging:Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses. BMC Nucl Med 7:3, 2007. PubMed
Salskov A, Tammisetti VS, Grierson J, Vesselle H: FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3′-deoxy-3′-[18F]fluorothymidine. Semin Nucl Med 37(6):429-39, 2007. Review. PubMed
