scholarly journals Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4710
Author(s):  
Noeen Malik ◽  
Shreya Bendre ◽  
Ralf Schirrmacher ◽  
Paul Schaffer

Background: Temperature-sensitive radiopharmaceutical precursors require lower reaction temperatures (<100 °C) during nucleophilic radiofluorination in order to avoid compound thermolysis, often resulting in sub-optimal radiochemical yields (RCYs). To facilitate nucleophilic aromatic substitution (SNAr) of nucleofuges commonly used in radiofluorination (e.g., nitro group), we explored the use of Lewis acids as nucleophilic activators to accelerate [18F]fluoride incorporation at lower temperatures, and thereby increasing RCYs for thermolabile activated precursors. Lewis acid-assisted radiofluorination was exemplified on the temperature-sensitive compound 1-(4-(4-morpholino-7-neopentyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-3-(6-nitropyridin-3-yl)urea (MN3PU, compound 3) targeting leucine-rich repeat kinase 2 (LRRK2), an important target in the study of Parkinson’s disease and various cancers. Methods: To a vessel containing dried K[18F]F-K222 complex, a solution of precursor MN3PU ((3), 1 mg; 1.8 μmol) and Lewis acid (6 μL of 0.2 μmol: chromium II chloride (A), ferric nitrite (B) or titanocene dichloride (C)) in 500 μL of N,N-dimethylformamide (DMF) (with 10% t-BuOH for B) were added. Reactions were stirred for 25 min at 90 °C. In parallel, reactions were conducted without the addition of Lewis acids for baseline comparison. After purification via preconditioned Sep-Pak C18 plus cartridges, aliquots were analyzed by analytical radio-HPLC. Results: Non-decay corrected radiochemical yields (ndc RCYs) for [18F]FMN3PU (7) were improved from 1.7 ± 0.7% (no addition of Lewis acids) to 41 ± 1% using Cr(II) and 37 ± 0.7% using Ti(II)-based Lewis acids, with radiochemical purities of ≥96% and molar activities (Am) of up to 3.23 ± 1.7 Ci/μmol (120 ± 1.7 GBq/μmol). Conclusion: RCYs of [18F]FMN3PU (7) improved from ~5% using conventional nucleophilic radiofluorination, up to 41 ± 1% using Lewis-acid supported SNAr.

ChemSusChem ◽  
2015 ◽  
Vol 8 (6) ◽  
pp. 1083-1087 ◽  
Author(s):  
Sarah Abou-Shehada ◽  
Matthew C. Teasdale ◽  
Steven D. Bull ◽  
Charles E. Wade ◽  
Jonathan M. J. Williams

ChemInform ◽  
2015 ◽  
Vol 46 (30) ◽  
pp. no-no
Author(s):  
Sarah Abou-Shehada ◽  
Matthew C. Teasdale ◽  
Steven D. Bull ◽  
Charles E. Wade ◽  
Jonathan M. J. Williams

Author(s):  
Kjell Jorner ◽  
Tore Brinck ◽  
Per-Ola Norrby ◽  
David Buttar

Hybrid reactivity models, combining mechanistic calculations and machine learning with descriptors, are used to predict barriers for nucleophilic aromatic substitution.


Synlett ◽  
2020 ◽  
Author(s):  
Xiaohua Liu ◽  
Yi Li ◽  
Hao Pan ◽  
Wang-Yuren Li ◽  
Xiaoming Feng

AbstractAn asymmetric organocatalytic nucleophilic aromatic substitution reaction of azlactones with electron-deficient aryls was established. A variety of α-aryl α-alkyl α-amino acid esters and peptides were obtained in decent yields and stereoselectivities. A new bifunctional catalytic mode involving charge-transfer interaction and hydrogen bonding is proposed to explain the enantioselectivity.


2007 ◽  
pp. 2264 ◽  
Author(s):  
Masahiro Ueno ◽  
Misato Yonemoto ◽  
Masahiro Hashimoto ◽  
Andrew E. H. Wheatley ◽  
Hiroshi Naka ◽  
...  

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