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Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer Malik, Noeen; Bendre, Shreya; Schirrmacher, Ralf; Schaffer, Paul
Abstract
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.
Item Metadata
| Title |
Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer
|
| Creator | |
| Publisher |
Multidisciplinary Digital Publishing Institute
|
| Date Issued |
2020-10-14
|
| Description |
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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| Subject | |
| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2020-11-26
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
CC BY 4.0
|
| DOI |
10.14288/1.0395071
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| URI | |
| Affiliation | |
| Citation |
Molecules 25 (20): 4710 (2020)
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| Publisher DOI |
10.3390/molecules25204710
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| Peer Review Status |
Reviewed
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| Scholarly Level |
Faculty
|
| Rights URI | |
| Aggregated Source Repository |
DSpace
|
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CC BY 4.0