Dataset Information

In vivo Characterization of Four ¹⁸F-Labeled S1PR1 Tracers for Neuroinflammation.

ABSTRACT:

Purpose

The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four ¹⁸F-labeled S1PR1 tracers (¹⁸F-TZ43113, ¹⁸F-TZ35104, ¹⁸F-TZ4877, and ¹⁸F-TZ4881) in a rat model of multiple sclerosis (MS).

Procedures

MicroPET studies of each tracer's uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats.

Results

All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was ¹⁸F-TZ4877 > ¹⁸F-TZ4881 > ¹⁸F-TZ35104 > ¹⁸F-TZ43113. ¹⁸F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of ¹⁸F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the rat brain.

Conclusion

Among these four new PET tracers, ¹⁸F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising ¹⁸F-labeled tracer for imaging S1PR1 in vivo.

SUBMITTER: Liu H

PROVIDER: S-EPMC7679043 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionGlucose 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 [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine.Materials and methodsBoth tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model.ResultsThe radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18% (n = 10) ([18F]fluorophenylglutamine) and 8.05 ± 3.25% (n = 5) ([18F]fluorobiphenylglutamine). In vitro 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 in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors.ConclusionWe investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]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 [18F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer. Advances in Knowledge and Implications for patient care: We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[18F]fluoroglutamine). [18F]FPG shows clear tumor uptake in vivo, has no in vivo 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.

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In vivo Characterization of Four ¹⁸F-Labeled S1PR1 Tracers for Neuroinflammation.

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Conclusion

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Dataset Information

In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation.

Purpose

Procedures

Results

Conclusion

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OmicsDI is part of the ELIXIR infrastructure

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In vivo Characterization of Four ¹⁸F-Labeled S1PR1 Tracers for Neuroinflammation.