Synthesis, Labeling, and Biological Evaluation of P2Y<sub>12</sub> Receptor Radioligands for Positron Emission Tomography Imaging of Neuroinflammation
The P2Y<sub>12</sub> receptor (P2Y<sub>12</sub>R) is a G-protein-coupled receptor whose expression level is directly correlated to microglial activation. Herein, we report on the design of a series of new P2Y<sub>12</sub>R ligands and the radiolabeling and characterization of two positron emission tomography (PET) tracers, [<sup>11</sup>C]<b>37</b> and [<sup>18</sup>F]<b>41</b>. These compounds were evaluated by autoradiography studies on rat brain slices exhibiting overexpression of human P2Y<sub>12</sub>Rs (AAV-<i>h</i>P2Y<sub>12</sub>R). Metabolism and biodistribution of [<sup>18</sup>F]<b>41</b> were evaluated ex vivo in healthy rats and indicated good metabolic stability with 41% of unchanged radioligand 1 h post injection and a limited crossing of the blood-brain barrier with a brain uptake of 0.02%ID/g 1 h post injection. In vivo PET imaging performed in the AAV-<i>h</i>P2Y<sub>12</sub>R rat model confirmed this low brain uptake, and no significant difference was found in the transfected (SUV<sub>mean</sub> 0.14 ± 0.01) versus contralateral (SUV<sub>mean</sub> 0.13 ± 0.01) striatum of the AAV-<i>h</i>P2Y<sub>12</sub>R model. Similar results were observed in healthy rats and in nonhuman primates. Additional studies in the presence of tariquidar led to a 3-4-fold increase in the [<sup>18</sup>F]<b>41</b> brain concentration, suggesting that [<sup>18</sup>F]<b>41</b> is a P-glycoprotein substrate. Future work will focus on improving radioligand design to enhance blood-brain barrier permeation and to reduce efflux transport.
Authors
- Nadja Van Camp (ORCID: https://orcid.org/0000-0002-2261-7314)
- Eugénie Pincemail
- Bertrand Kühnast (ORCID: https://orcid.org/0000-0002-5035-4072)
- Haneen Al-Hroub (ORCID: https://orcid.org/0000-0002-2033-0344)
- Sébastien Beuché
- Margot Corbel (ORCID: https://orcid.org/0000-0001-7297-2448)
- Alexis‐Pierre Bemelmans (ORCID: https://orcid.org/0000-0001-7605-5225)
- Mylène Richard (ORCID: https://orcid.org/0000-0003-0305-578X)
- H. Bensalah
- Caroline Denis
- Sébastien Goutal (ORCID: https://orcid.org/0000-0001-7797-0740)
- Marie Théry
- Alexandra Winkeler
- Maud Goislard (ORCID: https://orcid.org/0000-0002-8705-345X)
- Fabien Chauveau (ORCID: https://orcid.org/0000-0002-4177-741X)
- Marie‐Anne Peyronneau (ORCID: https://orcid.org/0000-0003-1520-4666)
- Christa Elisabeth Müller (ORCID: https://orcid.org/0000-0002-0013-6624)
- Hashem Ali M. Al Musawi (ORCID: https://orcid.org/0000-0003-0664-4942)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Bonn (DE)
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut des Maladies Neurodégénératives (FR)
- Centre de Recherche en Neurosciences de Lyon (FR)
- CEA Paris-Saclay (FR)
- Chemical Pharmaceutical Research Institute (BG)
- Laboratoire des Maladies Neurodégénératives (FR)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1021/acschemneuro.5c00187
- Citations
- 1
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.12
Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Centre National de la Recherche Scientifique
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives