Development of a novel radiobromine-labeled sigma-1 receptor imaging probe

Ogawa, Kenji; Masuda, Ryohei; Mizuno, Yoshiaki; Makino, Akihiro; Kozaka, Takashi; Kitamura, Yoshihisa; Kiyono, Yasushi; Shiba, Kazuhiro; Odani, Akira

doi:10.1016/j.nucmedbio.2018.03.005

Cited by 10 publications

(7 citation statements)

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“…Marked decreases in MC1 activity and reduced mitochondrial DNA levels were widely found in postmortem PD brain samples. [25][26][27][28] The development of selective PET radioligands [ 11 C] UCB-J for SV2A, 29 [ 11 C]SA-4503 for σ1R, 30 and [ 18 F] BCPP-EF for MC1, 31,32 allows for the in vivo investigation of presynaptic terminals and the mitochondrial/ER complex in neurodegenerative disorders. Here, we performed cross-sectional and longitudinal measurements using these 3 PET radioligands, 3-Tesla MRI, and a battery of clinical assessments in a cohort of early drugnaive PD patients.…”

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confidence: 99%

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug‐Naive Parkinson's Disease

et al. 2020

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A BS TRACT: Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [ 11 C]UCB-J, [ 11 C]SA-4503, and [ 18 F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [ 11 C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [ 11 C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [ 11 C]SA-4503 and [ 18 F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [ 11 C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.

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confidence: 99%

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug‐Naive Parkinson's Disease

et al. 2020

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“…The high radioactivity of radiobromine-labeled tracers in the blood is strongly related to the free bromide ions [17][18][19]. Therefore, the radioactivity in the blood can be used as an index of the debromination of radiobromine-labeled compounds in vivo [20]. In this study, the accumulation of [ 77 Br]9 in the blood was much higher than that of [ 125 I]ICO1686, which suggested that debromination occurred in vivo.…”

Section: Discussionmentioning

confidence: 68%

“…77 Br was produced by 77 Se(p,n) 77 Br reaction with and separated according to a previous study at the University of Fukui [20,30].…”

Section: Production Of Bromine-77mentioning

confidence: 99%

A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma

Fawwaz

Mishiro

Nishii³

et al. 2021

Pharmaceuticals

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Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC50 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

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“…5B), by using 77 Br which has a longer half-life (57.0 h) instead of 76 Br. 54,55) These probes showed properties similar to those of the corresponding radioiodinelabeled probes.…”

Section: Sigma-1 Receptor Targeted Probesmentioning

confidence: 77%

Development of Diagnostic and Therapeutic Probes with Controlled Pharmacokinetics for Use in Radiotheranostics

Ogawa

2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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The word "theranostics," a portmanteau word made by combining "therapeutics" and "diagnostics," refers to a personalized medicine concept. Recently, the word, "radiotheranostics," has also been used in nuclear medicine as a term that refer to the use of radioisotopes for combined imaging and therapy. For radiotheranostics, a diagnostic probe and a corresponding therapeutic probe can be prepared by introducing diagnostic and therapeutic radioisotopes into the same precursor. These diagnostic and therapeutic probes can be designed to show equivalent pharmacokinetics, which is important for radiotheranostics. As imaging can predict the absorbed radiation dose and thus the therapeutic and side effects, radiotheranostics can help achieve the goal of personalized medicine. In this review, I discuss the use of radiolabeled probes targeting bone metastases, sigma-1 receptor, and α V β 3 integrin for radiotheranostics.

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Development of a novel radiobromine-labeled sigma-1 receptor imaging probe

Cited by 10 publications

References 31 publications

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug‐Naive Parkinson's Disease

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug‐Naive Parkinson's Disease

A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma

Development of Diagnostic and Therapeutic Probes with Controlled Pharmacokinetics for Use in Radiotheranostics

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