Synthesis of PET probe O6-[(3-[11C]methyl)benzyl]guanine by Pd0-mediated rapid C-[11C]methylation toward imaging DNA repair protein O6-methylguanine-DNA methyltransferase in glioblastoma

Koyama, Hiroko; Ikenuma, Hiroshi; Toda, Hiroshi; Kondo, Goro; Hashimoto, Masaki; Kato, Masaaki; Abe, Jiro; Yamada, Takashi; Wakabayashi, Toshihiko; Ito, Kengo; Natsume, Atsushi; Suzuki, Masaaki

doi:10.1016/j.bmcl.2017.03.045

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…Researchers also evaluated the efficacy of applying advanced MRI techniques to determine the status of MGMT methylation in GBMs, including diffusion imaging [18], diffusion tensor imaging [19, 20], and perfusion imaging [19–21]. Positron emission tomography (PET) was also studied to discover predictive markers for MGMT-expressed glioblastoma in vitro [22]. All these studies proposed that the MGMT molecular aspects of GBMs can be characterized quite convincingly by MRI-derived tumor features or by a PET imaging agent.…”

Section: Introductionmentioning

confidence: 99%

Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics

et al. 2017

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“…3 ) that could be radiolabeled using a Pd 0 -mediated cross-coupling reaction. We decided to introduce the methyl group on the meta- position based on the several reports showing the para -position on the benzene ring substituted with an electron-donating group is more susceptible to oxidative metabolism than the meta -position (Koyama et al 2017 ; Smith et al 1996 ; Thompson 2001 ; Van De Waterbeemd et al 2001 ). GSK’962, the enantiomer of GSK’963, has a lower RIPK1 inhibitory activity, suggesting that the steric configuration near the chiral carbon atom affect RIPK1 inhibitory activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of a novel PET ligand, a GSK’963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain

Ikenuma,

Ogata,

Koyama

et al. 2023

EJNMMI radiopharm. chem.

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Background Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer’s disease (AD) has been reported; RIPK1 is involved in microglia’s phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1. Results (S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK’963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK’963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK’963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK’963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47–115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively. Conclusions We synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK’963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required.

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“…carbonylation was also established by the Pd II -mediated reaction of[ 11 C]CO and common arylboronate at ambient temperature under atmospheric pressure using conventional helium carrier gas. Likely, the rapid C-[ 11 C]carboxylation under atmospheric pressure was promoted by the use of Rh I catalyst.Recently, we have further applied our rapid C-methylation to the synthesis of 10-O-p-[ 11 C] methylbenzyl ginkgolide B (128) andO 6 -[(3-[ 11C]methyl)benzyl]guanine (129) as newly designed PET probes for the study of brain permeability of ginkgolides in monkeys and rats[104] and for conducting the imaging of DNA repair protein O 6 -methylguanine-DNA methyltransferase in glioblastoma[105], respectively. Further, novel rapid C-methylation methodology have also been employed for the syntheses of novel PET probes by us and our collaborators, such as 4 0 -[11 C] methylflavone ([ 11 C]-130) [106], [ 11 C]cetrozole ( 11 C-incorporated aromatase inhibitor) ([ 11 C]-131) [107], [ 11 C]thiamine ([ 11 C]-132) [108], [ 11 C]fursultiamine ([ 11 C]-133) [108], and 11 C-labeled GN8 ([ 11 C]-134) for prion imaging [109].…”

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Green Process of Three-Component Prostaglandin Synthesis and Rapid <sup>11</sup>C Labelings for Short-Lived PET Tracers

Suzuki¹,

Koyama²,

Ishii³

et al. 2018

Green Process of Three-Component Prostaglandin Synthesis and Rapid ≪sup>11Self Cite

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General synthesis of prostaglandins (PGs) has been accomplished based on a one-pot three-component coupling using a combination of organocopper or organozincate conjugate addition to 4-hydroxy-2-cyclopentenone followed by trapping of resulting enolate with an organic halide. Based on the use of this synthetic methodology, biologically significant PG derivatives including ent-Δ 7-PGA 1 , 15SAPNIC ([ 3 H]APNIC), and 15R-TIC have also been synthesized. Ultimately, organozincate conjugate addition combined with the enolate trapping by an organic triflate results in practical green threecomponent coupling comprising the use of stoichiometric amounts of three components (enone, α-and ω-side chains in a nearly 1:1:1 ratio) without using HMPA and heavy metals. General methodology for introducing short-lived 11 C and 18 F radionuclides into carbon frameworks has been established by developing rapid C-[ 11 C]methylation and C-[ 18 F]fluoromethylation using Pd 0-mediated rapid cross-coupling between [ 11 C]methyl iodide and an organotributylstannane or organoboronate; or [ 18 F]fluoromethyl bromide and organoboronate, respectively, allowing the synthesis of a wide variety of biologically significant and disease-oriented PET probes such as 15R-[ 11 C]TIC. Moreover, Pd IImediated rapid C-[ 11 C]carbonylation using [ 11 C]CO and organoboronate at ambient temperature under atmospheric pressure using conventional helium carrier gas has been explored. Further, C-[ 11 C]carboxylation has been promoted using [ 11 C]CO 2 and organoboronate with Rh I catalyst under atmospheric pressure.

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Synthesis of PET probe O6-[(3-[11C]methyl)benzyl]guanine by Pd0-mediated rapid C-[11C]methylation toward imaging DNA repair protein O6-methylguanine-DNA methyltransferase in glioblastoma

Cited by 6 publications

References 26 publications

Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics

Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics

Synthesis and evaluation of a novel PET ligand, a GSK’963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain

Green Process of Three-Component Prostaglandin Synthesis and Rapid <sup>11</sup>C Labelings for Short-Lived PET Tracers

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