PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Yangchun Xin,Xuyi Yue,Zhiqin Li,Arabinda K Choudhary,Diane C Chugani,Shaohui Zhang,Sigrid A Langhans,Hua Li,Hancheng Cai

doi:10.1038/s41598-020-60728-6

Abstract

In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)-L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. 1-L-[18F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice with constitutive actvation of the Smoothened (Smo) receptor using a PerkinElmer G4 PET-X-Ray scanner. Medulloblastoma showed significant and specific accumulation of 1-L-[18F]FETrp. 1-L-[18F]FETrp also showed significantly higher tumor uptake than its D-enantiomer, 1-D-[18F]FETrp. The uptake of 1-L-[18F]FETrp in the normal brain tissue was low, suggesting that 1-L-[18F]FETrp may prove a valuable PET imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors.

Highlights

In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors
While PET imaging with 1-L-[18F]FETrp shows promise for detecting brain tumors[32], previous studies have been limited to mouse xenograft models using established cell lines and primary tumor cells from adult patients, not taking into account limitations imposed by the blood brain barrier (BBB)
Mouse brains processed for histological hematoxylin and eosin (H&E) staining after PET imaging confirmed the presence of cerebellar tumors in the symptomatic mice (Fig. 2C), suggesting that 1-L-[18F]FETrp could serve as a PET imaging probe to detect medulloblastoma

Summary

Introduction

In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. We evaluated 1-L-[18F]FETrp for PET imaging of the most common malignant pediatric brain cancer medulloblastoma in an immunecompetent, transgenic mouse model for the Shh subgroup in which tumors occur spontaneously[38]. Using the Smo/Smo mouse model with constitutive activation of the Smoothened (Smo) receptor and a model for the Shh subgroup of medulloblastoma, we show that 1-L-[18F]FETrp accumulated in cerebellar tumors but not in normal brain. Future studies will determine whether 1-L-[18F]FETrp is suitable for clinical translation as a PET imaging probe for medulloblastoma and possibly other brain tumors in pediatric and adult populations

Methods

Results

Conclusion