One-Pot Radiosynthesis of [18F]Anle138b—5-(3-Bromophenyl)-3-(6-[18F]fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazole—A Potential PET Radiotracer Targeting α-Synuclein Aggregates

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-03, Vol.28 (6), p.2732
• Main Authors: Orlovskaya, Viktoriya V., Fedorova, Olga S., Viktorov, Nikolai B., Vaulina, Daria D., Krasikova, Raisa N.
• Format: Article
• Language: English
• Subjects: 6-[18F]fluoropiperonal; [18F]anle138b; Aggregates; Animal models; Automation; Blood-brain barrier; Cell culture; Cycloaddition; Decay; Dopamine; Drug development; Fluorides; Fluorine; Fluorine isotopes; fluorine-18; Half-life; Labeling; Medical imaging; Metabolism; Metabolites; Neurons; Oligomerization; one-pot synthesis; Optimization; Parkinson's disease; Pharmacokinetics; Positron emission; Prion protein; Proteins; Pyrazole; Pyrazoles; Radioactive tracers; radiofluorination; Synuclein; α-synuclein
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28062732

Availability of PET imaging radiotracers targeting α-synuclein aggregates is important for early diagnosis of Parkinson’s disease and related α-synucleinopathies, as well as for the development of new therapeutics. Derived from a pyrazole backbone, 11C-labelled derivatives of anle138b (3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole)—an inhibitor of α-synuclein and prion protein oligomerization—are currently in active development as the candidates for PET imaging α-syn aggregates. This work outlines the synthesis of a radiotracer based on the original structure of anle138b, labelled with fluorine-18 isotope, eminently suitable for PET imaging due to half-life and decay energy characteristics (97% β+ decay, 109.7 min half-life, and 635 keV positron energy). A three-step radiosynthesis was developed starting from 6-[18F]fluoropiperonal (6-[18F]FP) that was prepared using (piperonyl)(phenyl)iodonium bromide as a labelling precursor. The obtained 6-[18F]FP was used directly in the condensation reaction with tosylhydrazide followed by 1,3-cycloaddition of the intermediate with 3′-bromophenylacetylene eliminating any midway without any intermediate purifications. This one-pot approach allowed the complete synthesis of [18F]anle138b within 105 min with RCY of 15 ± 3% (n = 3) and Am in the range of 32–78 GBq/µmol. The [18F]fluoride processing and synthesis were performed in a custom-built semi-automated module, but the method can be implemented in all the modern automated platforms. While there is definitely space for further optimization, the procedure developed is well suited for preclinical studies of this novel radiotracer in animal models and/or cell cultures.