Design of a ¹⁸F-labeled purinergic P2Y₁ receptor (P2Y₁R) ligand for brain imaging

Objectives: Purine nucleotides such as ATP and ADP are important extracellular signaling molecules in almost all tissues. Via P2Y₁R activation they mediate brain functions by trophic effects like differentiation and proliferation but also via fast synaptic transmission. The understanding of its role in brain disorders is limited because of lack of suitable brain-penetrating P2Y₁R-selective drugs. Chao and co workers recently reported the first non-nucleotidic, diarylurea ligands with high affinity and selectivity for the P2Y₁R^[1]. We selected this scaffold for the development a ¹⁸F labeled P2Y₁R ligand for brain imaging.

Methods: Based on the lead compounds 1-3 (K_i = 6-8 nM),^[1] we designed derivative 5, suitable for aliphatic radiofluorination using the corresponding tosyl precursor 4. The radiolabeling was systematically optimized (eg. phase transfer catalyst, solvent, temperature, amount of precursor and heating method) and [¹⁸F]5 successfully provided for subsequent evaluation. The lead structure was further modified by fluorinating pyridine at the 2-position, replacing the urea subunit C with 2 aminothiazole, and substituting ring D with various fluoroaromatic and non-aromatic rings.

Results: Reference compound 5 has been synthesized from the tosylate 4 in 62% yield. Under optimized conditions, [¹⁸F]5 has been obtained in high radiochemical yield (30%) and purity (≥99%) at a specific activity of ~182 GBq/µmol. A series of 30 new fluorinated derivatives has been synthesized.

Conclusions: The first ¹⁸F-labeled P2Y₁R ligand, [¹⁸F]5 has been successfully synthesized. To evaluate the newly designed compounds, an in vitro binding assay using stably transfected P2Y₁R-1321N1 cells and [¹⁸F]5 is currently developed.

Literature: [1] Chao et al. J. Med. Chem. 2013, 56, 1704−1714