Radiosynthesis and biological evaluation of the new PDE10A radioligand [¹⁸F]AQ28A

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• 作者：Sally Wagner ; Rodrigo Teodoro ; Winnie Deuther-Conrad ; Mathias Kranz ; Matthias Scheunemann ; Steffen Fischer ; Barbara Wenzel ; Ute Egerland ; Norbert Hoefgen ; Jö ; rg Steinbach and Peter Brust
• 刊名：Journal of Labelled Compounds and Radiopharmaceuticals
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：60
• 期：1
• 页码：36-48
• 全文大小：1252K
• ISSN：1099-1344

文摘

Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[¹⁸F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([¹⁸F]AQ28A). [¹⁸F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[¹⁸F]F-K_2.2.2-carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [¹⁸F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol⁻¹) for further evaluation. Initially, we investigated the binding of [¹⁸F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [¹⁸F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [¹⁸F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.