Quinuclidine and DABCO Enhance the Radiofluorination of 5‐Substituted 2‐Halopyridines

• Published in: European journal of organic chemistry Vol. 2017; no. 45; pp. 6593 - 6603
• Main Authors: Naumiec, Gregory R., Cai, Lisheng, Lu, Shuiyu, Pike, Victor W.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 08.12.2017; Wiley Subscription Services, Inc
• Subjects: Additives; Amines; Biomedical materials; Chemistry; Chemistry, Organic; Cyclotrons; Fluoridation; Fluorides; Fluorinated compounds; Fluorine; Halopyridines; Homology; In vivo methods and tests; Labelling; Medical imaging; Medical research; Organocatalysis; Physical Sciences; Positron emission; Radiofluorination; Reactive intermediates; Science & Technology; Substitutes; Tomography; Tracers; Fluorine; ENANTIOMERS; FULLY AUTOMATED RADIOSYNTHESIS; FLUORINATION; Organocatalysis; NUCLEOPHILIC AROMATIC-SUBSTITUTION; POSITRON-EMISSION-TOMOGRAPHY; Reactive intermediates; TRACER; Radiofluorination; Halopyridines; Fluorinated compounds; PET RADIOLIGAND
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201700970

Positron emission tomography (PET) is an important molecular imaging technique for medical diagnosis, biomedical research and drug development. PET tracers for molecular imaging contain β+‐emitting radionuclides, such as carbon‐11 (t1/2 = 20.4 min) or fluorine‐18 (t1/2 = 109.8 min). The [18F]2‐fluoropyridyl moiety features in a few prominent PET radiotracers, not least because this moiety is usually resistant to unwanted radiodefluorination in vivo. Various methods have been developed for labeling these radiotracers from cyclotron‐produced no‐carrier‐added [18F]fluoride ion, mainly based on substitution of a leaving group, such as halide (Cl or Br), or preferably a better leaving group, such as nitro or trimethylammonium. However, precursors with a good leaving group are sometimes more challenging or lengthy to prepare. Methods for enhancing the reactivity of more readily accessible 2‐halopyridyl precursors are therefore desirable, especially for early radiotracer screening programs that may require the quick labeling of several homologous radiotracer candidates. In this work, we explored a wide range of additives for beneficial effect on nucleophilic substitution by [18F]fluoride ion in 5‐substituted 2‐halopyridines (halo = Cl or Br). The nucleophilic cyclic tertiary amines, quinuclidine and DABCO, proved effective for increasing yields to practically useful levels (> 15 %). Quinuclidine and DABCO likely promote radiofluorination through reversible formation of quaternary ammonium intermediates. Quinuclidine and DABCO are the best organic bases identified, to promote the nucleophilic substitution by [18F]fluoride ion in 5‐substituted 2‐halopyridines (halo = Cl or Br), and to increase the radiochemical yields to practically useful levels (> 15 %). A quaternary ammonium salt was proposed as the reaction intermediate.