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

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 60; no. 1; pp. 36 - 48
• Main Authors: Wagner, Sally, Teodoro, Rodrigo, Deuther‐Conrad, Winnie, Kranz, Mathias, Scheunemann, Matthias, Fischer, Steffen, Wenzel, Barbara, Egerland, Ute, Hoefgen, Norbert, Steinbach, Jörg, Brust, Peter
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-01-2017
• Subjects: 18F‐labeled radioligand; animal PET/MR; Animals; automated synthesis; Brain - diagnostic imaging; bromo precursor; Female; Fluorine Radioisotopes - chemistry; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Ligands; Mice; nitro precursor; PDE10 radioligand; Phosphoric Diester Hydrolases - metabolism; Positron-Emission Tomography; Protein Binding; Quinoxalines - chemical synthesis; Quinoxalines - pharmacokinetics; Radiopharmaceuticals - adverse effects; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Sprague-Dawley; Swine; Tissue Distribution; animal PET/MR; PDE10 radioligand; automated synthesis; 18F-labeled radioligand; nitro precursor; bromo precursor
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3471

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‐K2.2.2‐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.
A fully automated radiosynthesis of [18F]AQ28A was achieved starting from the nitro precursor AQ63. In vitro autoradiography demonstrated the suitability of [18F]AQ28A as a specific radioligand to visualize the PDE10A protein in different species. Animal PET revealed a specific accumulation of [18F]AQ28A in the PDE10A‐rich striatum, along with a lack of specific accumulation after blocking PDE10A with MP‐10.