Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

Abstract

Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. a-11 C-methyl-L-tryptophan ( 11 C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11 C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18 F-fluoroethyl)-L-tryptophan ( 18 F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18 F-FETrp in patient-derived xenograft mouse models and compared them with 11 C-AMT uptake. Methods: Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18 F-FETrp and 11 C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared. Results: 18 F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11 C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18 F-FETrp showed higher tumoral SUV than 11 C-AMT in all 3 tumor types tested. The radiation dosimetry for 18 F-FETrp determined from the mouse data compared favorably with the clinical 18 F-FDG PET tracer. Conclusion: 18 F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

“…In naïve mice with B16-F10 melanoma tumors that received PD-L1 and Cytotoxic T lymphocyte-associated protein 4 (CTLA-4 or CD152) directed ICI therapy, high tracer uptake was observed in the tumor upon irradiation, suggesting that PD-1 PET can be used for ICI treatment monitoring. Natarajan et al injected a 64 Cu-labeled anti-mouse PD-1 Ab in Foxp3 + LuciDTR4 mice, a mouse model that contains high expressing PD-1 Foxp3 + regulatory T cells, bearing (Juhasz et al 2006(Juhasz et al , 2009(Juhasz et al , 2012Zitron et al 2013;Michelhaugh et al 2017;Guastella et al 2016) A2aR…”

“…Furthermore, these results indicate that [ 11 C]AMT-PET might be used for stratification of true progression versus pseudoprogression. In a recent preclinical study, in vivo tumor targeting of a newly developed IDO1 tracer, 1-(2-[ 18 F]-fluoroethyl)-L-tryptophan ([ 18 F]FETrp), was compared with [ 11 C] AMT and increased SUVs were observed for [ 18 F] FETrp compared with [ 11 C] AMT in lung, breast, and brain xenografts (Michelhaugh et al 2017). Target specificity of [ 18 F] FETrp has also been demonstrated in preclinical prostate, lung, breast, and glioma tumor models by Xin et al with a significantly higher tumor uptake than in low IDO1 expressing healthy tissues, and a correlation of in vitro cell binding and in vivo [ 18 F] FETrp tumor uptake.…”

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

“…, a tryptophan analog, has been successfully used to evaluate the increased tryptophan metabolism through KP in patients with brain tumors [18][19][20][21][22][23][24][25] . However, the short half-life of the carbon-11 isotope has limited the broad applications in clinical research and significant effort has been made in developing 18 F-labeled tryptophan tracers 15,17,[32][33][34][35][36] . Recent in vitro and in vivo studies suggest that a novel PET tracer, 1-(2-…”

“…, might have similar transport and metabolic properties as [ 11 C]AMT ( Fig. 1), and could be used to assess abnormal tryptophan metabolism via the KP in brain tumors [32][33][34] .…”

“…While PET imaging with 1-L-[ 18 F]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). In medulloblastoma, while changes in the BBB in the WNT form allow passage of chemotherapeutic agents into the brain and have high cure rates, the BBB is intact in the chemoresistant Shh form 37 .…”