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3'-[¹⁸F]Fluoro-3'-Deoxythymidine ([¹⁸F]-FLT) as Positron Emission Tomography Tracer for Imaging Proliferation in a Murine B-Cell Lymphoma Model and in the Human Disease

Departments of Nuclear Medicine [U. S., A. B., B. N., S. S., S. N. R], Internal Medicine I [M. W., M. Ba.], Internal Medicine III [M. Bo., G. M.], Pathology [F. L.], University of Ulm, 89081 Ulm, Germany and Vienna Biocenter, Institute of Molecular Biology, University of Vienna, A-1030 Vienna [E. W.]

Here we describe the evaluation of 3'-[¹⁸F]fluoro-3'-deoxythymidine {[¹⁸F]-FLT} as a tracer for positron emission tomography (PET) in a murine model of B-cell lymphoma and in human malignant lymphoma. The human B-cell line DoHH2 expressed high levels of active thymidine kinase 1 (TK-1) as the key enzyme of [¹⁸F]-FLT metabolism. Immunostaining confirmed high levels of TK-1 in DoHH2 derived xenograft tumors in SCID/SCID mice. In vitro studies demonstrated a time-dependent uptake of [¹⁸F]-FLT, an efficient phosphorylation to the respective monophosphate and the incorporation of [¹⁸F]-FLT into the perchloric acid insoluble fraction in DoHH2 cells, indicating the incorporation of this tracer into the DNA. After incubation with [¹⁸F]FLT for 240 min, 12.5% ± 1.0% of radioactivity applied to the medium was intracellularly trapped in DoHH2 cells. Specific accumulation of [¹⁸F]-FLT in the malignant cell clone was confirmed in biodistribution studies in SCID/SCID mice bearing DoHH2-derived tumors. The percentage of injected dose of [¹⁸F]-FLT per gram of tumor tissue correlated with the tumor-proliferation index as evaluated in BrdUrd-labeling experiments. In a pilot study of 11 patients with both indolent and aggressive lymphoma, [¹⁸F]-FLT was suitable and comparable to [¹⁸F]-FDG in the ability to detect malignant lesions by PET scan. Furthermore, we found a close correlation (r = 0.95, P < 0.005) of the [¹⁸F]-FLT standardized uptake values with the Ki67-labeling index of tissue biopsies (n = 10) in these patients. These results suggest that [¹⁸F]-FLT represents a novel tracer for PET that enables imaging of proliferation in human lymphoma in vivo.

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