Synthesis and biological evaluation of novel PET tracers [18F]AG120 &amp; [18F]AG135 for imaging mutant isocitrate dehydrogenase 1 expression

Wang, Tingting; Lin, Qingyu; Zhang, Yingying; Xu, Zhan; Shi, Dai; Cheng, Yuan; Fu, Zhequan; Tan, Handong; Cheng, Dengfeng; Shi, Hongcheng

doi:10.1016/j.bmc.2021.116525

Cited by 6 publications

(12 citation statements)

References 22 publications

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“…To date, a few radiotracers for scintigraphic imaging of mIDH have been designed based on three chemical scaffolds, headed by the two clinically available drugs, ivosidenib (AG-120, phenyl-glycine) and enasidenib (AG-221, triazine), together with a butyl-phenyl sulfonamide class of mIDH1 inhibitors. However, none of these have been clinically validated so far [20][21][22][23]. Starting from the phenyl-glycine scaffold, compounds with high inhibitory potentials for mIDH1 (IC 50 value <50 nM) were synthesised as mixtures of stereoisomers and radiolabelled with fluorine-18 or iodine radioisotopes (I, II, III, and IV, Figure 1) [21,23].…”

Section: Introductionmentioning

confidence: 99%

“…However, none of these have been clinically validated so far [20][21][22][23]. Starting from the phenyl-glycine scaffold, compounds with high inhibitory potentials for mIDH1 (IC 50 value <50 nM) were synthesised as mixtures of stereoisomers and radiolabelled with fluorine-18 or iodine radioisotopes (I, II, III, and IV, Figure 1) [21,23]. The preliminary results showed stability against dehalogenation in vivo, but several drawbacks, such as the lack of a diastereoselective (radio)synthesis, low radiochemical yields, and insufficient brain uptake, suggested a need for further developments regarding this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

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Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

et al. 2022

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Isocitrate dehydrogenases (IDHs) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukaemia, chondrosarcoma, and intrahepatic cholangiocarcinoma). These mutated variants of IDH (mIDH) acquire a neomorphic activity, namely, conversion of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate involved in tumourigenesis. Thus, mIDHs have emerged as highly promising therapeutic targets, and several mIDH specific inhibitors have been developed. However, the evaluation of mIDH status, currently performed by biopsy, is essential for patient stratification and thus treatment and follow-up. We report herein the development of new radioiodinated and radiofluorinated analogues of olutasidenib (FT-2102) as tools for noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging of mIDH1 up- and dysregulation in tumours. Nonradiolabelled derivatives 2 and 3 halogenated at position 6 of the quinolinone scaffold were synthesised and tested in vitro for their inhibitory potencies and selectivities in comparison with the lead compound FT-2102. Using a common organotin precursor, (S)-[125I]2 and (S)-[18F]3 were efficiently synthesised by radio-iododemetallation and copper-mediated radiofluorination, respectively. Both radiotracers were stable at room temperature in saline or DPBS solution and at 37 °C in mouse serum, allowing future planning of their in vitro and in vivo evaluations in glioma and chondrosarcoma models.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

et al. 2022

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“…Indeed, target engagement by several inhibitors as measured by cellular thermal shift assays (CETSA) in a glioma cell line transfected with IDH1 R132H has been shown to correlate poorly with inhibition in enzymatic assays (R 2 = 0.18), although a stronger correlation (R 2 = 0.54–0.78) was observed for inhibition in cellular assays with the same cell line [ 60 ]. Since previous studies with radiolabeled inhibitors have generally found a good agreement between IC 50 values for suppression and K d values for binding to the mutated enzymes in cells as well [ 61 , 62 ], the potency determined in cellular assays may still be a useful surrogate for the affinity of inhibitors for the mutated enzymes. However, prediction of their affinity for the wildtype enzymes based on existing data is more difficult because the selectivity for inhibition of mutant over wildtype enzymes has exclusively been determined in enzymatic assays.…”

Section: Considerations For the Development Of Midh-selective Pet-tra...mentioning

confidence: 99%

“…For example, tumor cell lines engineered to overexpress a mutated IDH isoform may be well suited for assessing how potently an inhibitor suppresses cellular 2-HG production but could be less suitable for certain cellular uptake studies with radioligands. Thus, while most radioligands prepared from mIDH-selective inhibitors showed significantly higher uptake into mIDH-transfected cell lines compared to the corresponding non-transfected cell lines, much less pronounced differences were typically observed when comparing uptake into cell lines carrying a native IDH mutation and the corresponding mIDH-knockout cell lines [ 61 , 62 , 69 ] (for details, see Section 7 ). Taken together, these findings suggest that at least some of the apparently selective cellular uptake observed in the transfected cell lines may reflect factors that would not contribute to tumor accumulation in glioma patients, such as a higher overall enzyme concentration in transfected compared to non-transfected cells rather than selective binding to mutant enzymes.…”

Section: Considerations For the Development Of Midh-selective Pet-tra...mentioning

confidence: 99%

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

2023

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Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target. However, current clinical methods for detecting mutated IDH (mIDH) require invasive tissue sampling and cannot be used for follow-up examinations or longitudinal studies. PET imaging could be a promising approach for non-invasive assessment of the IDH status in gliomas, owing to the availability of various mIDH-selective inhibitors as potential leads for the development of PET tracers. In the present review, we summarize the rationale for the development of mIDH-selective PET probes, describe their potential applications beyond the assessment of the IDH status and highlight potential challenges that may complicate tracer development. In addition, we compile the major chemical classes of mIDH-selective inhibitors that have been described to date and briefly consider possible strategies for radiolabeling of the most promising candidates. Where available, we also summarize previous studies with radiolabeled analogs of mIDH inhibitors and assess their suitability for PET imaging in gliomas.

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“…That is why monofluorinated cycloalkane (cyclobutane, cyclohexane) derivatives were used as PET tracers in all the previous studies. In any case, such compounds are somewhat beyond the scope of this review since their synthesis does not typically involve fluori- [195,196] tyrosine derivative 685 bearing a [ 18 F] 3-fluorocyclobutyl moiety as a metabolically stable prosthetic group, [207] radiolabeled pan-tropomyosin receptor kinase (Trk) inhibitor 686, [467] and IDH1 inhibitor 687 [468] (an analog of another known IDH1 inhibitor Ivosidenib bearing the 3,3-difluorocyclobutyl moiety, see section 6.1, with 18 F label at the pyridine ring was also suggested [469] ) (Figure 68).…”

Section: Positron Emission Tomography (Pet) Imaging Agentsmentioning

confidence: 99%

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

et al. 2022

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The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

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Synthesis and biological evaluation of novel PET tracers [18F]AG120 & [18F]AG135 for imaging mutant isocitrate dehydrogenase 1 expression

Cited by 6 publications

References 22 publications

Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

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