Nucleophilic substitution of nitro groups by [18F]fluoride in methoxy-substituted ortho-nitrobenzaldehydes—A systematic study

Shen, Bin; Löffler, Dirk; Reischl, Gerald; Machulla, H.-J.; Zeller, Klaus‐Peter

doi:10.1016/j.jfluchem.2008.10.003

Cited by 14 publications

(7 citation statements)

References 18 publications

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“…Decomposition of MN3PU (3) via thermolytic degradation of the urea moiety in polar-aprotic solvents (DMF/DMSO) and at higher temperatures (>100 °C), led to significant challenges in obtaining adequate RCYs for subsequent biodistribution studies. We were not able to obtain higher RCYs as reported for similar small-molecule tracers reported elsewhere [ 5 , 6 , 7 ].…”

Section: Discussioncontrasting

confidence: 67%

“…In heteroaromatic compounds containing a pyridine ring, the N-atom exerts a considerable activating effect on the LG. Even in the presence of strong electron donating groups (EDG), such as -OCH 3 and -CH 3 at the - para or - ortho position to the LG, very high radiochemical yields (RCYs) (>80%) were observed at high temperatures (>110 °C) [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Malik

Bendre²,

Schirrmacher

et al. 2020

Molecules

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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.

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Section: Discussioncontrasting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Malik

Bendre²,

Schirrmacher

et al. 2020

Molecules

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“…The tris(methoxy)‐substituted salicylaldehyde was synthesized by using hexamethylenetetramine through a Duff reaction as reported previously 12. The salicylaldehyde was then reacted with trans ‐1,2‐cyclohexanediamine and subsequently Ni(OAc) 2 · 4H 2 O to afford Ni salen complex 1 (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Electronic Structure Evaluation of an Oxidized Tris(methoxy)‐Substituted Ni Salen Complex

et al. 2015

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The Ni salen complex N,N′-bis(2,3,4-trimethoxysalicylidene)-1,2-cyclohexane-(1R,2R)-diamine nickel(II) (1), containing ortho-, meta-, and para-methoxy-substituted phenolate moieties, was prepared. Electrochemical studies revealed that the first oxidation of 1 occurs at a similar potential to a previously reported Ni salen complex NiSal tBu,OMe , employing an ortho-tBu and para-methoxy substitution pattern (M. Orio et al., Angew. Chem. Int. Ed. 2010, 49, 4989), demonstrating the counteracting effects of the methoxy substituent depending on ring location (ortho/para vs. meta). The second oxidation occurred at a much lower potential (E 1/2 2 -E 1/2 1 = 0.11 V) for 1, in comparison to NiSal tBu,OMe , suggesting significant localization of the [a]

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“…Good radiochemical yields (RCY) are known to be obtained in case of isotopic exchange ( 18 F/ 19 F) and substitution of nitro and tetramethylammonium 1–3. In general, rates of the S N Ar process and maxium radiochemical yields increase with the lowered electrophilicity of the LG‐substituted aromatic carbon atom of the precursor 4…”

Section: Introductionmentioning

confidence: 99%

Nucleophilic [¹⁸F]Fluorination and subsequent decarbonylation of methoxy‐substituted nitro‐ and halogen‐benzenes activated by one or two formyl groups

Shen

Löffler

Reischl

et al. 2010

Labelled Comp Radiopharmac

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As model reactions for the introduction of 18 F into protected aromatic amino acids, the replacement of NO 2 , Cl, Br and F by [ 18 F]fluoride in 2-isophthalaldehyde and 2-terephthalaldehyde derivatives which model 18 F-DOPA and 18 F-tyrosine was investigated by comparing labelling yields and reaction rates with those of corresponding mono-aldehyde compounds. All isophthalaldehydes showed maximum radiochemical yields (79 to 86%) at 1401C and in comparison with the corresponding mono-aldehydes the reaction proceeded faster. At lower temperature the reaction already resulted in high yields, e.g. 2-nitroisophthalaldehyde was labelled with a yield of 78% at 251C after 7 min, whereas 2-nitrobenzaldehyde only reached a yield of 1.7% under the same reaction conditions. The 18 F/NO 2 exchange in nitroterephthalaldehydes proceeded more slowly and with lower radiochemical yields when compared with corresponding isophthalaldehydes and monoaldehydes.

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Nucleophilic substitution of nitro groups by [18F]fluoride in methoxy-substituted ortho-nitrobenzaldehydes—A systematic study

Cited by 14 publications

References 18 publications

Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Electronic Structure Evaluation of an Oxidized Tris(methoxy)‐Substituted Ni Salen Complex

Nucleophilic [¹⁸F]Fluorination and subsequent decarbonylation of methoxy‐substituted nitro‐ and halogen‐benzenes activated by one or two formyl groups

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Nucleophilic substitution of nitro groups by [18F]fluoride in methoxy-substituted ortho-nitrobenzaldehydes—A systematic study

Cited by 14 publications

References 18 publications

Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer

Electronic Structure Evaluation of an Oxidized Tris(methoxy)‐Substituted Ni Salen Complex

Nucleophilic [18F]Fluorination and subsequent decarbonylation of methoxy‐substituted nitro‐ and halogen‐benzenes activated by one or two formyl groups

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Nucleophilic [¹⁸F]Fluorination and subsequent decarbonylation of methoxy‐substituted nitro‐ and halogen‐benzenes activated by one or two formyl groups