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| Home > Publications database > [18F]R91150: A promising candidate for 5-HT2A-PET imaging |
| Home > Publications database > [18F]R91150: A promising candidate for 5-HT2A-PET imaging |
| Contribution to a conference proceedings/Journal Article | FZJ-2026-03773 |
; ; ; ; ;
2025
Elsevier Science
Amsterdam [u.a.]
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Please use a persistent id in citations: doi:10.1016/j.nucmedbio.2025.109380
Abstract: Introduction: Serotonergic 5-HT2A receptors are widely expressed in the cortex and other forebrain structures, where they play a crucial role for cognitive and emotional processes. Dysfunction of these receptors is associated with various neuropsychiatric and neurodegenerative disorders, making them an attractive target for positron emission tomography (PET) imaging. The radiolabeled 5-HT2A receptor antagonist [18F]R91150 has shown promising in vitro binding properties but in vivo data on this radioligand are still lacking. Furthermore, existing protocols enable its preparation only in low activity yields. Therefore, this work aimed to develop an optimized procedure for the production of [18F]R91150 and to evaluate its imaging properties. Methods: [18F]R91150 was prepared by “alcohol-enhanced” Cu-mediated radiofluorination with the NextGen Cu-complex Cu(4-PhPy)4(ClO4)2 from either a Boc-protected (1) or unprotected (2) pinacol boronate precursor. To this end, [18F]fluoride was trapped on a QMA carbonate cartridge and eluted with a solution of Et4NOTf in MeOH. After evaporation of MeOH, a solution of precursor 1 (10 μmol) or 2 (5 μmol) and Cu(4-PhPy)4(ClO4)2 (10 μmol) in 2:1 DMI/nBuOH (1.2 mL) was added and the reaction mixture was stirred at 110 °C for 10 min. In the case of precursor 1, the corresponding radiolabeled intermediate was deprotected with 6 M HCl at 80 °C for 10 min before [18F]R91150 was isolated by HPLC and formulated as an injectable solution. If precursor 2 was used, the crude [18F]R91150 was purified by SPE followed by HPLC. Biodistribution studies were performed by μPET imaging in healthy C57BL/6 mice (whole body distribution) and Long-Evans rats (brain distribution). In addition, in vivo blocking or displacement studies in Long-Evans rats were conducted with non-labeled R91150 (1 mg/kg), the 5-HT2A receptor antagonists altanserin or ketanserin (1.5 mg/kg) and the 5-HT2C receptor antagonist SB242084 (0.1 mg/kg). Results: The two-step radiosynthesis from Boc-protected precursor 1 afforded [18F]R91150 in high activity yields (AYs) of 24±2% within 90–100 min. Using unprotected precursor 2, the synthesis time could be reduced to 65−75 min while maintaining AYs of 12±2%. Both approaches produced the tracer in high molar activities of up to 240 GBq/μmol. μPET imaging in mice demonstrated high in vivo stability and predominantly hepatobiliary excretion, with high tracer uptake in bile and intestine. In rats, the cerebral tracer distribution was consistent with the known expression pattern of 5-HT2A receptors and previous in vitro autoradiography studies with rat brain slices. Furthermore, pre-treatment or displacement with the 5-HT2A receptor ligands R91150, altanserin or ketanserin significantly reduced tracer accumulation in the cortex by 25–50%, while pretreatment with the 5-HT2C receptor ligand SB242084 had no effect on the cerebral radioactivity distribution. Conclusions: The optimized radiolabeling protocol enabled efficient synthesis of [18F]R91150 from both Boc-protected and unprotected precursors, with improved activity yields and/or reduced synthesis time compared to previous methods. Preclinical in vivo studies demonstrated specific and selective binding of the radioligand to cortical 5-HT2A receptors, further establishing [18F]R91150 as a promising candidate for PET imaging of 5-HT2A receptors in the brain.
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