Synthesis and biological evaluation of 18F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging

Chiotellis, Aristeidis; Mu, Linjing; Müller, Adrienne; Selivanova, Svetlana V.; Keller, Claudia; Schibli, Roger; Krämer, Stefanie-Dorothea; Ametamey, Simon M.

doi:10.1016/j.ejmech.2013.10.054

Cited by 29 publications

(29 citation statements)

References 41 publications

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“…Compound 3a was then subjected to 2-allylation following Danishefsky's methodology which adequately afforded 4. The phthalyl group was then cleaved using methylhydrazine 20 For the synthesis of the 5OH-2FMTRP (Scheme 3), we envisioned that the desired hydroxymethyl functionality could derive from the reduction of 2-formyl-5-hydroxytryptophan, obtained by the SeO 2 oxidation of a suitably protected 1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid as previously reported. 34,35 We additionally aimed at fully protecting the amino nitrogen with two electron withdrawing Boc groups to prevent potential intramolecular attack on the electrophilic carbon of the precursor, to form back the rigid 6-membered β-carboline ring.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

et al. 2016

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Aiming at developing mechanism-based amino acid (18)F-PET tracers for tumor imaging, we synthesized two (18)F-labeled analogues of 5-hydroxy-l-[β-(11)C]tryptophan ([(11)C]5HTP) whose excellent in vivo performance in neuroendocrine tumors is mainly attributed to its decarboxylation by aromatic amino acid decarboxylase (AADC), an enzyme overexpressed in these malignancies. Reference compounds and precursors were synthesized following multistep synthetic approaches. Radiosynthesis of tracers was accomplished in good radiochemical yields (15-39%), high specific activities (45-95 GBq/μmol), and excellent radiochemical purities. In vitro cell uptake was sodium-independent and was inhibited ≥95% by 2-amino-2-norbornanecarboxylic acid (BCH) and ∼30% by arginine. PET imaging in mice revealed distinctly high tumor/background ratios for both tracers, outperforming the well-established O-(2-[(18)F]fluoroethyl)tyrosine ([(18)F]FET) tracer in a head-to-head comparison. Biological evaluation revealed that the in vivo performance is most probably independent of any interaction with AADC. Nevertheless, the excellent tumor visualization qualifies the new tracers as interesting probes for tumor imaging worthy for further investigation.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

et al. 2016

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“…These tracers are based on analogues of L- and D-tyrosine 20, 21 , or a racemic mixture of fluoropropyl tryptophan 22 , as well as the fluoro-ethoxy analogue used in the present study, 18 F-L-FEHTP 24 . We chose 18 F-L-FEHTP as a PET tracer that targets LAT1 since the biodistribution data in mice indicated the highest uptake in non-tumor tissue was in the pancreas, and the PET images in this study did not show appreciable background signal.…”

Section: Discussionmentioning

confidence: 99%

Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas

et al. 2016

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Purpose: In diabetes, pancreatic beta cell mass declines significantly prior to onset of fasting hyperglycemia. This decline may be due to endoplasmic reticulum (ER) stress, and the system L amino acid transporter LAT1 may be a biomarker of this process. In this study, we used 5-(2- 18F-fluoroethoxy)-L-tryptophan ( 18F-L-FEHTP) to target LAT1 as a potential biomarker of beta cell function in diabetes. Procedures: Uptake of 18F-L-FEHTP was determined in wild-type C57BL/6 mice by ex vivo biodistribution. Both dynamic and static positron emission tomography (PET) images were acquired in wild-type and Akita mice, a model of ER stress-induced diabetes, as well as in mice treated with streptozotocin (STZ). LAT1 expression in both groups of mice was evaluated by immunofluorescence microscopy. Results: Uptake of 18F-L-FEHTP was highest in the pancreas, and static PET images showed highly specific pancreatic signal. Time-activity curves showed significantly reduced 18F-L-FEHTP uptake in Akita mice, and LAT1 expression was also reduced. However, mice treated with STZ, in which beta cell mass was reduced by 62%, showed no differences in 18F-L-FEHTP uptake in the pancreas, and there was no significant correlation of 18F-L-FEHTP uptake with beta cell mass. Conclusions: 18F-L-FEHTP is highly specific for the pancreas with little background uptake in kidney or liver. We were able to detect changes in LAT1 in a mouse model of diabetes, but these changes did not correlate with beta cell function or mass. Therefore, 18F-L-FEHTP PET is not a suitable method for the noninvasive imaging of changes in beta cell function during the progression of diabetes.

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“…9 Recently, a more efficient radiolabeling has been performed by 18 F-fluoroalkylation in different positions of tryptophan. [10][11][12] The major aim of this study was to find out, whether an activation of the carbocycle of the indole moiety is possible in such a way that isotopic 18 F-exchange via a nucleophilic aromatic substitution (S N Ar) becomes possible. For this, the influence of the substitution pattern of the fluorine and the activating carbonyl group on the RCY and chemical stability were of high interest.…”

Section: Introductionmentioning

confidence: 99%

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

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Neumaier

Meleán

et al. 2015

Bioorganic & Medicinal Chemistry

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Synthesis and biological evaluation of 18F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging

Cited by 29 publications

References 41 publications

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas

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

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Synthesis and biological evaluation of 18F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging

Cited by 29 publications

References 41 publications

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[18F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[18F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas

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

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Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[¹⁸F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging