Radiosynthesis of 4-[ 18 F]fluoro- l -tryptophan by isotopic exchange on carbonyl-activated precursors

Weiss, Philipp; Neumaier, Bernd; Meleán, Johnny Castillo; Schäfer, Dominique; Coenen, Heinz H.

doi:10.1016/j.bmc.2015.06.073

Cited by 19 publications

(15 citation statements)

References 32 publications

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“…These products represent highly desirable 18 F-heterocycles that have proven extremely challenging to access in high specific activity, and could serve as valuable scaffolds for radiotracer and drug development. 36 …”

Section: Resultsmentioning

confidence: 99%

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

et al. 2016

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Synthesis of non-activated electron-rich and sterically hindered 18F-arenes remains a major challenge due to limitations of existing radiofluorination methodologies. Herein, we report on our mechanistic investigations of spirocyclic iodonium(III) ylide precursors for arene radiofluorination, including their reactivity, selectivity, and stability with no-carrier-added [18F]fluoride. Benchmark calculations at the G2[ECP] level indicate that pseudorotation and reductive elimination at iodine(III) can be modeled well by appropriately selected dispersion-corrected density functional methods. Modeling of the reaction pathways show that fluoride–iodonium(III) adduct intermediates are strongly activated and highly regioselective for reductive elimination of the desired [18F]fluoroarenes (difference in barriers, ΔΔG‡ > 25 kcal·mol−1). The advantage of spirocyclic auxiliaries is further supported by NMR spectroscopy studies, which bolster evidence for underlying decomposition processes which can be overcome for radiofluorination of iodonium(III) precursors. Using a novel adamantyl auxiliary, sterically hindered iodonium ylides have been developed to enable highly efficient radiofluorination of electron-rich arenes, including fragments of pharmaceutically relevant nitrogen-containing heterocycles and tertiary amines. Furthermore, this methodology has been applied for the syntheses of the radiopharmaceuticals 6-[18F]fluoro-meta-tyrosine ([18F]FMT, 11 ± 1% isolated radiochemical yield, non-decay-corrected (RCY, n.d.c.; n = 3), and meta-[18F]fluorobenzylguanidine ([18F]mFBG, 14 ± 1% isolated RCY, n.d.c., n = 3) which cannot be directly radiolabeled using conventional nucleophilic aromatic substitution with [18F]fluoride.

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Section: Resultsmentioning

confidence: 99%

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

et al. 2016

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“…Several novel 18 F-labeled tryptophan derivatives have been developed and tested as potential PET tracers for tumor imaging (27)(28)(29)(30)(31)(32). Although most compounds showed tumor uptake, they were not designed to target IDO1, IDO12, or TDO2 activity.…”

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confidence: 99%

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

et al. 2016

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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.

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“…To explore this idea, we synthesized 18 F-labeled derivatives of tryptophan devoid of a methyl substituent at the 1-position or the alpha position. In fact, 4-[ 18 F]F-Trp, 5-[ 18 F]F-Trp and 6-[ 18 F]F-Trp have been reported before, but limited examples of radiofluorination at position 7 exist 24, 31-33, 37, 38. As shown in Scheme 3A, starting from iodinated or brominated tryptophan derivatives, the boronic ester group was successfully introduced at positions 4, 5, 6, and 7 of the indole ring via Miyaura borylation ( 18a - d ).…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, tryptophan could be metabolized to serotonin that regulates various neuro-activities and insulin secretion (Fig 1) 21. Clearly, radiolabeled tryptophan and its derivatives could potentially offer a non-invasive method to study tryptophan metabolism in various diseases 22-33. As mentioned above, we have been particularly interested in developing a PET agent to study IDO1 activity during cancer progression or treatment.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 5-[¹⁸F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents

Giglio¹,

Fei²,

Wang³

et al. 2017

Theranostics

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Indoleamine 2,3-dioxygenase (IDO1) plays a special role in the biology of various cancer types, because it breaks down the essential amino acid tryptophan for immune cell activation. Upregulation of IDO1 significantly correlates with the number of various T cell types in tumor tissues in melanoma and other cancers, suggesting that IDO expression is linked with effective and ineffective ('exhausted') immune response in cancer. Based on the reported IDO inhibitors (α-Methylated and indole-N-methylated tryptophan (Trp)), here we report the synthesis of potential IDO1 imaging agents through direct introduction of 18F into the tryptophan aromatic ring. Overall, the resulting PET agents could be obtained in high radiochemical purity (>97%) with labeling yield ranges from 4.2-14.9% decay corrected yield. Using Trp as the model compound, our results also demonstrate that 18F could be directly introduced to the Trp backbone at the 4, 5, 6, and 7 position. Moreover, our initial imaging study suggests that 5-[18F]F-L-α-methyl tryptophan (5-[18F]F-AMT) holds great potential for cancer imaging. The success of this approach will provide researchers easy access to a library of Trp/Trp-derivative based PET agents for biomedical research, including potential IDO1 targeted imaging.

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Radiosynthesis of 4-[ 18 F]fluoro- l -tryptophan by isotopic exchange on carbonyl-activated precursors

Cited by 19 publications

References 32 publications

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

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

Synthesis of 5-[¹⁸F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents

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Radiosynthesis of 4-[ 18 F]fluoro- l -tryptophan by isotopic exchange on carbonyl-activated precursors

Cited by 19 publications

References 32 publications

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides

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

Synthesis of 5-[18F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents

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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

Synthesis of 5-[¹⁸F]Fluoro-α-methyl Tryptophan: New Trp Based PET Agents