Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Glucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [<jats:sup>18</jats:sup>F]fluorophenylglutamine and [<jats:sup>18</jats:sup>F]fluorobiphenylglutamine</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p>Both tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [<jats:sup>3</jats:sup>H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [<jats:sup>18</jats:sup>F]fluorophenylglutamine and [<jats:sup>18</jats:sup>F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18 % (n=10) ([<jats:sup>18</jats:sup>F]fluorophenylglutamine) and 8.05 ± 3.25 % (n=5) ([<jats:sup>18</jats:sup>F]fluorobiphenylglutamine). <jats:italic>In vitro</jats:italic> inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the <jats:italic>in vivo</jats:italic> experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [<jats:sup>18</jats:sup>F]FBPG in the mice PC-3 xenograft and a moderate uptake of [<jats:sup>18</jats:sup>F]FPG in the PC-3 tumors.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We investigated the imaging potential of two novel PET radiotracers [<jats:sup>18</jats:sup>F]FPG and [<jats:sup>18</jats:sup>F]FBPG. [<jats:sup>18</jats:sup>F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [<jats:sup>18</jats:sup>F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer.</jats:p></jats:sec><jats:sec><jats:title>Advances in Knowledge and Implications for patient care</jats:title><jats:p>We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing <jats:italic>in vivo</jats:italic> defluorination, which can occur with alkyl labelled tracers (e.g. (2<jats:italic>S</jats:italic>,4<jats:italic>R</jats:italic>)4-[<jats:sup>18</jats:sup>F]fluoroglutamine). [<jats:sup>18</jats:sup>F]FPG shows clear tumor uptake <jats:italic>in vivo</jats:italic>, has no <jats:italic>in vivo</jats:italic> defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.</jats:p><jats:fig id="ufig1" position="anchor" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="948372v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine

“…Research has led to the development of both therapeutic and diagnostic compounds targeting their transporters and metabolic enzymes [25][26][27][28] . Due to the drawbacks of [ 18 F]FDG and the "glutamine addiction" of several tumors, different PET radiotracers based on the glutamine backbone have been developed [5][6][7][8][10][11][12][13]16,17 . In this study, we developed and characterized [ 18 derivatives.…”

“…All these aspects led to the development of glutamine-based PET tracers e.g. [16][17][18][19][20] . As an isotopic variant, [ 11 C]glutamine has identical physicochemical properties to normal (which was not certified by peer review) is the author/funder.…”