In Vivo Uptake and Metabolism of α-[¹¹C]Methyl-l-Tryptophan in Human Brain Tumors

Abstract

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. a-[ 11 C]Methyl-L-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution (VD 0 ) and the metabolic rate constant (k 3 0 ) were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD 0 values, suggesting impaired blood-brain barrier, while k 3 0 values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k 3 0 . In contrast, oligodendrogliomas showed high VD 0 values but lower k 3 0 as compared with normal cortex. In astrocytic tumors, low grade was associated with high k 3 0 and lower VD 0 , while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/ or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

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

“…Nevertheless, the high 18 F-FETrp uptake in the bladder and pancreas suggests that this tracer would not allow visualization of tumors in these organs because of high background activity. Despite the differences in distribution, both tracers demonstrated similarly low and continuous brain accumulation, suggesting that 18 F-FETrp will be suitable for the imaging of intracranial brain tumors as previously established with 11 C-AMT (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

“…Our previous PET studies demonstrated differential 11 C-AMT transport and trapping in human gliomas, lung cancer, and breast cancer, tumors that expressed both the L-type amino acid transporter 1 and IDO1 (23,26,(45)(46)(47). However, the widespread use of 11 C-AMT for cancer imaging is not feasible because of its short half-life and tedious radiosynthesis.…”

“…11 C-AMT PET studies were further extended to nonepileptogenic primary and metastatic brain tumors (19)(20)(21)(22). These studies demonstrated variably high 11 C-AMT uptake in gliomas (18,23,24) and meningiomas (21) and showed strong prognostic value for survival in patients with recurrent glioblastoma (20). Furthermore, 11 C-AMT uptake characteristics distinguished recurrent gliomas from radiation injury (25) and glioblastoma from metastatic brain tumors (26), allowing tryptophan PET imaging as a possible clinical diagnostic tool.…”

Characterization of the Kynurenine Pathway in Human Neurons

“…Uyttenhove et al (2003) showed that a majority of human tumors constitutively express IDO. Another study demonstrated that gliomas and glioneuronal tumors have an elevated TRP uptake and metabolism (Juhasz et al, 2006). This high TRP metabolism by low-grade tumors is very likely to be associated with an activation of the kynurenine pathway, which represents a mechanism regulating tumor cell growth and persistence (Juhasz et al, 2006).…”

In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1

“…6 We have previously demonstrated tryptophan metabolism in a variety of human brain tumors using α-[ 11 C]methyl-l-trypto phan (AMT) positron emission tomography (PET) imaging. [7][8][9][10] AMT is an amino acid radiotracer, which can measure expression and activity of indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting step of the kynurenine pathway of tryptophan catabolism, can enable tumor cells to effectively evade the host's immune response. The potential role of this system was investigated in meningiomas.…”