Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer
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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/20/4710 |
| _version_ | 1827704269078265856 |
|---|---|
| author | Noeen Malik Shreya Bendre Ralf Schirrmacher Paul Schaffer |
| author_facet | Noeen Malik Shreya Bendre Ralf Schirrmacher Paul Schaffer |
| author_sort | Noeen Malik |
| collection | DOAJ |
| 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 (S<sub>N</sub>Ar) of nucleofuges commonly used in radiofluorination (e.g., nitro group), we explored the use of Lewis acids as nucleophilic activators to accelerate [<sup>18</sup>F]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-7<i>H</i>-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[<sup>18</sup>F]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 <i>N,N</i>-dimethylformamide (DMF) (with 10% <i>t</i>-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 [<sup>18</sup>F]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 (A<sub>m</sub>) of up to 3.23 ± 1.7 Ci/μmol (120 ± 1.7 GBq/μmol). Conclusion: RCYs of [<sup>18</sup>F]FMN3PU (7) improved from ~5% using conventional nucleophilic radiofluorination, up to 41 ± 1% using Lewis-acid supported S<sub>N</sub>Ar. |
| first_indexed | 2024-03-10T15:37:19Z |
| format | Article |
| id | doaj.art-452ee256a43b484dacfdf91a5c5b328a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:37:19Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-452ee256a43b484dacfdf91a5c5b328a2023-11-20T17:06:48ZengMDPI AGMolecules1420-30492020-10-012520471010.3390/molecules25204710Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 RadiotracerNoeen Malik0Shreya Bendre1Ralf Schirrmacher2Paul Schaffer3Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, CanadaMolecular Oncology, BCCRC, 675 W 10th Ave, Vancouver, BC V5Z 1L3, CanadaLife Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, CanadaLife Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, CanadaBackground: 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 (S<sub>N</sub>Ar) of nucleofuges commonly used in radiofluorination (e.g., nitro group), we explored the use of Lewis acids as nucleophilic activators to accelerate [<sup>18</sup>F]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-7<i>H</i>-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[<sup>18</sup>F]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 <i>N,N</i>-dimethylformamide (DMF) (with 10% <i>t</i>-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 [<sup>18</sup>F]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 (A<sub>m</sub>) of up to 3.23 ± 1.7 Ci/μmol (120 ± 1.7 GBq/μmol). Conclusion: RCYs of [<sup>18</sup>F]FMN3PU (7) improved from ~5% using conventional nucleophilic radiofluorination, up to 41 ± 1% using Lewis-acid supported S<sub>N</sub>Ar.https://www.mdpi.com/1420-3049/25/20/4710Lewis acidsradiofluorinationnucleophilic aromatic substitutionsLRRK2 |
| spellingShingle | Noeen Malik Shreya Bendre Ralf Schirrmacher Paul Schaffer Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer Molecules Lewis acids radiofluorination nucleophilic aromatic substitutions LRRK2 |
| title | Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer |
| title_full | Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer |
| title_fullStr | Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer |
| title_full_unstemmed | Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer |
| title_short | Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer |
| title_sort | lewis acid facilitated radiofluorination of mn3pu a lrrk2 radiotracer |
| topic | Lewis acids radiofluorination nucleophilic aromatic substitutions LRRK2 |
| url | https://www.mdpi.com/1420-3049/25/20/4710 |
| work_keys_str_mv | AT noeenmalik lewisacidfacilitatedradiofluorinationofmn3pualrrk2radiotracer AT shreyabendre lewisacidfacilitatedradiofluorinationofmn3pualrrk2radiotracer AT ralfschirrmacher lewisacidfacilitatedradiofluorinationofmn3pualrrk2radiotracer AT paulschaffer lewisacidfacilitatedradiofluorinationofmn3pualrrk2radiotracer |