{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:21:24Z","timestamp":1760239284880,"version":"build-2065373602"},"reference-count":9,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T00:00:00Z","timestamp":1602633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000015","name":"Canadian Cancer Society Research Institute","doi-asserted-by":"publisher","award":["705808"],"award-info":[{"award-number":["705808"]}],"id":[{"id":"10.13039\/501100000015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Temperature-sensitive radiopharmaceutical precursors require lower reaction temperatures (&lt;100 \u00b0C) 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\u2019s 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 \u03bcmol) and Lewis acid (6 \u03bcL of 0.2 \u03bcmol: chromium II chloride (A), ferric nitrite (B) or titanocene dichloride (C)) in 500 \u03bcL of N,N-dimethylformamide (DMF) (with 10% t-BuOH for B) were added. Reactions were stirred for 25 min at 90 \u00b0C. 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 \u00b1 0.7% (no addition of Lewis acids) to 41 \u00b1 1% using Cr(II) and 37 \u00b1 0.7% using Ti(II)-based Lewis acids, with radiochemical purities of \u226596% and molar activities (Am) of up to 3.23 \u00b1 1.7 Ci\/\u03bcmol (120 \u00b1 1.7 GBq\/\u03bcmol). Conclusion: RCYs of [18F]FMN3PU (7) improved from ~5% using conventional nucleophilic radiofluorination, up to 41 \u00b1 1% using Lewis-acid supported SNAr.<\/jats:p>","DOI":"10.3390\/molecules25204710","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T08:14:50Z","timestamp":1602922490000},"page":"4710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lewis Acid-Facilitated Radiofluorination of MN3PU: A LRRK2 Radiotracer"],"prefix":"10.3390","volume":"25","author":[{"given":"Noeen","family":"Malik","sequence":"first","affiliation":[{"name":"Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shreya","family":"Bendre","sequence":"additional","affiliation":[{"name":"Molecular Oncology, BCCRC, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7098-3036","authenticated-orcid":false,"given":"Ralf","family":"Schirrmacher","sequence":"additional","affiliation":[{"name":"Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada"},{"name":"Cross Cancer Institute, MICF, University of Alberta, 11560 University Ave, Edmonton, AB T6G 1Z2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Schaffer","sequence":"additional","affiliation":[{"name":"Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada"},{"name":"Department of Radiology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada"},{"name":"Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Scott, J.H.P., and Hockley, B.G. (2012). Radiochemical Syntheses: Radiopharmaceuticals for Positron Emission Tomography, John Wiley & Sons. Inc.","DOI":"10.1002\/9781118140345"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1021\/acscentsci.7b00195","article-title":"18F-Deoxyfluorination of Phenols via Ru \u03c0-Complexes","volume":"3","author":"Beyzavi","year":"2017","journal-title":"ACS Cent. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1002\/anie.201912567","article-title":"Site-Selective Late-Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts","volume":"59","author":"Xu","year":"2020","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Orlovskaya, V.V., Modemann, D.J., Kuznetsova, O.F., Fedorova, O.S., Urusova, E.A., Kolks, N., Neumaier, B., Krasikova, R.N., and Zlatopolskiy, B.D. (2019). Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under \u201cMinimalist\u201d Conditions. 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Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/20\/4710\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:21:23Z","timestamp":1760178083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/20\/4710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,14]]},"references-count":9,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["molecules25204710"],"URL":"https:\/\/doi.org\/10.3390\/molecules25204710","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2020,10,14]]}}}