Development of ¹⁸F-Labeled Radiotracers for PET Imaging of the Adenosine A_2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

• Main Authors: Thu Hang Lai, Susann Schröder, Magali Toussaint, Sladjana Dukić-Stefanović, Mathias Kranz, Friedrich-Alexander Ludwig, Steffen Fischer, Jörg Steinbach, Winnie Deuther-Conrad, Peter Brust, Rareş-Petru Moldovan
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: International Journal of Molecular Sciences
• Subjects: adenosine receptors; A2A receptor; fluorine-18; positron emission tomography; vipadenant
• Online Access: https://www.mdpi.com/1422-0067/22/5/2285
• ISSN: 1661-6596; 1422-0067

The adenosine A_2A receptor (A_2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A_2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (<b>PPY</b>). Among those, the highly affine 4-fluorobenzyl derivate (<b>PPY1</b>; <i>K</i>_i(<i>h</i>A_2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (<b>PPY2</b>; <i>K</i>_i(<i>h</i>A_2AR) = 2.1 nM) were chosen for ¹⁸F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [¹⁸F]<b>PPY</b><b>1</b> and [18F]<b>PPY2</b> in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [¹⁸F]<b>PPY</b><b>2</b> on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.