Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review
25
Citation
76
Reference
10
Related Paper
Citation Trend
Keywords:
Biodistribution
Kynurenine pathway
Indoleamine 2,3-dioxygenase
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. Surgical specimens from 22 patients with meningiomas were used for cellular, immunological and molecular techniques (immunofluorescence, western blotting, RT-PCR and biochemical assay of enzyme activity) to investigate the expression and activity of IDO. In addition, PET imaging was obtained preoperatively in 10 patients using the tracer α-[ ( 11) C]methyl-L-tryptophan (AMT) which interrogates the uptake and metabolism of tryptophan. Strong AMT accumulation was noted in all meningiomas by PET imaging indicating in vivo tryptophan uptake. Freshly-resected meningiomas expressed both LAT1, the tryptophan transporter system and IDO, demonstrating an active kynurenine pathway. Dissociated meningioma cells lost IDO expression. Following exposure to interferon-γ (IFNγ), IDO expression was reinduced and could be blocked by a selective IDO1 inhibitor. IDO activity may represent an element of local self-protection by meningiomas and could be targeted by emerging IDO1 inhibitors.
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Catabolism
Cite
Citations (34)
Introduction: Tryptophan, an essential amino acid, follows important metabolic pathways for protein, niacin and serotonin synthesis (Fig 1). Tryptophan depletion and accumulation of some of its neurotoxic metabolites have both physical and psychological implications. The kynurenine pathway is a major pathway for tryptophan degradation and for the synthesis of the metabolites kynurenine and quinolinic acid. Assessment of tryptophan metabolism is generally hampered by the non availability of analytical techniques for these substances.
Kynurenine pathway
Tryptophan Metabolism
Kynurenic acid
Metabolic pathway
Anthranilic acid
Niacin
Cite
Citations (0)
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Cite
Citations (67)
Indoleamine 2,3-dioxygenase
Kynurenic acid
Kynurenine pathway
Picolinic acid
Catabolism
Pathogenesis
Cite
Citations (0)
Accumulation of quinolinic acid and L-kynurenine occurs in the brain and/or blood following immune activation, and may derive from L-tryptophan following induction of indoleamine 2,3-dioxygenase and other kynurenine-pathway enzymes. In the present study a survey of various cell lines derived from either brain or systemic tissues showed that, while all cells examined responded to interferon-gamma by increased conversion of L-[13C6]tryptophan into L-kynurenine (human: B-lymphocytes, neuroblastoma, glioblastoma, lung, liver, kidney; rat brain: microglia, astrocytes and oligodendrocytes), only macrophage-derived cells (peripheral-blood mononuclear cells; THP-1, U-937) and certain liver cells (SKHep1) synthesized [13C6]quinolinic acid. Tumour necrosis factor-alpha enhanced the effects of interferon-gamma in THP-1 cells. Norharmane, 6-chloro-DL-tryptophan and 4-chloro-3-hydroxyanthranilate attenuated quinolinic acid formation by THP-1 cells with IC50 values of 51 microM, 58 microM and 0.11 microM respectively. Norharmane and 6-chloro-DL-tryptophan attenuated L-kynurenine formation with IC50 values of 43 microM and 51 microM respectively, whereas 4-chloro-3-hydroxyanthranilate had no effect on L-kynurenine accumulation. The reductions in L-kynurenine and quinolinic acid formation are consistent with the reports that norharmane is an inhibitor of indoleamine 2,3-dioxygenase, 6-chloro-DL-tryptophan is metabolized through the kynurenine pathway, and 4-chloro-3-hydroxyanthranilate is an inhibitor of 3-hydroxyanthranilate 3,4-dioxygenase. These results suggest that many tissues may contribute to the production of L-kynurenine following indoleamine 2,3-dioxygenase induction and immune activation. Quinolinic acid may be directly synthesized from L-tryptophan in both macrophages and certain types of liver cells, although uptake of quinolinic acid precursors from blood may contribute to quinolinic acid synthesis in cells that cannot convert L-kynurenine into quinolinic acid.
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Cite
Citations (97)
Indoleamine 2,3-dioxygenase
Kynurenic acid
Kynurenine pathway
Plasmodium berghei
Picolinic acid
Cite
Citations (22)
Increased kynurenine pathway metabolism has been implicated in the aetiology of the AIDS dementia complex (ADC). The rate limiting enzyme for this pathway is indoleamine 2,3-dioxygenase (IDO). We tested the efficacy of different strains of HIV-1 (HIV1-BaL, HIV1-JRFL and HIV1-631) to induce IDO in cultured human monocyte-derived macrophages (MDM). A significant increase in both IDO protein and kynurenine synthesis was observed after 48 h in MDM infected with the brain derived HIV-1 isolates, laboratory adapted (LA) HIV1-JRFL, and primary isolate HIV1-631. In contrast, almost no kynurenine production or IDO protein was evident in MDM infected with the high replicating macrophage tropic LA strain, HIV1-BaL. The induction of IDO and kynurenine synthesis by HIV1-JRFL and HIV1-631 declined to baseline levels by day-8 post-infection. Together, these results indicate that only selected strains of HIV-1 are capable of inducing IDO synthesis and subsequent oxidative tryptophan catabolism in MDM.
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Catabolism
Infectivity
Cite
Citations (31)
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Cite
Citations (80)
Many neurologic diseases are related to autoimmune dysfunction and a variety of molecules or reaction pathways are involved in the regulation of immune function of the nervous system. Soluble CD83 (sCD83) is the soluble form of CD83, a specific marker of mature dendritic cell, which has recently been shown to have an immunomodulatory effect. Indoleamine 2, 3-dioxygenase (IDO; corresponding enzyme intrahepatic, tryptophan 2,3-dioxygenase, TDO), a rate-limiting enzyme of extrahepatic tryptophan kynurenine pathway (KP), participates in the immunoregulation through a variety of mechanisms solely or with the synergy of sCD83, and the imbalances of metabolites of KP were associated with immune dysfunction. With the complement of sCD83 to IDO-KP a previously known immunomodulatory axis, this review focused on an expanded neuroimmunomodulation axis: sCD83-IDO-KP and its involvement in nervous system diseases.
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Cite
Citations (12)
Indoleamine 2,3-dioxygenase
Kynurenine pathway
Cite
Citations (27)