18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma.

Silvia Valtorta,Denise Toscani,Federica Vacondio,Matteo Grioni,Giuseppe Taurino,Arianna Brevi,Franca Zanardi,Martina Chiu,Angela Coliva,Livia Ruffini,Matteo Bellone,Rosa Maria Moresco,Andrea Sartori,Nicola Giuliani,Ovidio Bussolati

doi:10.3389/fonc.2021.760732

Abstract

The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.

Highlights

Multiple myeloma (MM) is a hematological disease characterized by the accumulation of malignant plasma cells (PC) into and, more rarely, outside the bone marrow (BM) [1]
We carried out the stereospecific synthesis of 4-FGln [1], to be used both for in vitro biological assays and as a reference compound in radio-HPLC analyses
Based on previously reported procedures [14], we carried out the stereospecific synthesis of 4-FGln (Supplementary Figures 1–5) to be used both for in vitro biological assays and as a reference compound in radio-HPLC analyses

Summary

Introduction

Multiple myeloma (MM) is a hematological disease characterized by the accumulation of malignant plasma cells (PC) into and, more rarely, outside the bone marrow (BM) [1]. [18F]FDG uptake yields both false positive and false negative lesions, and only 60– 70% of patients with active MM are positive for [18F]FDG PET [4, 5]. These data support the need for additional imaging methods to assess skeletal involvement and monitoring the effect of treatment. To this purpose, several other PET tracers, such as choline and methionine, have been proposed [6, 7]

Methods

Results

Conclusion