Design and Synthesis of Novel PET Radiotracers for Imaging Sphingosine-1-Phosphate Receptor 5 (S1PR5) in the Brain
Sphingosine-1-phosphate receptor-5 (S1PR5) is highly expressed in oligodendrocytes and it plays an important role in neurodegenerative disorders like multiple sclerosis. We designed, synthesized, and determined the binding potencies of 27 novel S1PR5 ligands. Four radiotracers [<sup>11</sup>C]<b>7</b>, [<sup>18</sup>F]<b>7a</b>, [<sup>11</sup>C]<b>12a</b>, and [<sup>18</sup>F]<b>12b</b> were synthesized for the characterization of their <i>in vitro</i> and <i>in vivo</i> binding properties. [<sup>18</sup>F]<b>7a</b> had good rat brain uptake with 0.62%ID/g at 5 min, while the other three radiotracers had lower brain uptake. [<sup>18</sup>F]<b>7a</b> had K<sub>d</sub> values of 2.2, 4.6, and 27.6 nM for recombinant human S1PR5 cell membranes, C57BL/6 mouse brain, and human cerebral cortex, respectively. Pretreatment with S1PR5 potent modulators effectively impacted rodent brain uptake of [<sup>18</sup>F]<b>7a</b>. Cuprizone-fed mice had reduced [<sup>18</sup>F]<b>7a</b> brain uptake, reflecting the loss of oligodendrocytes and decreased S1PR5 expression. [<sup>18</sup>F]<b>7a</b> also showed good brain uptake and retention in macaque, and no radiometabolites entered the rat brain, further supporting its potential as a promising radiotracer for imaging S1PR5 in the brain.
Authors
- Jiawen Lang (ORCID: https://orcid.org/0000-0003-2718-6485)
- Caroline Guglielmetti (ORCID: https://orcid.org/0000-0003-0305-1631)
- Lin Qiu (ORCID: https://orcid.org/0009-0001-9956-9496)
- Shu‐xian Xu
- Ying‐Hwey Nai (ORCID: https://orcid.org/0000-0002-6634-8785)
- Matthew R. Brier (ORCID: https://orcid.org/0000-0001-5987-8705)
- Zhude Tu (ORCID: https://orcid.org/0000-0003-0325-835X)
- Joel S. Perlmutter (ORCID: https://orcid.org/0000-0003-3263-8917)
- Wenjuan Zhou (ORCID: https://orcid.org/0000-0003-4012-7893)
- Yanbo Yu (ORCID: https://orcid.org/0000-0002-6687-9850)
- Tianyu Huang (ORCID: https://orcid.org/0000-0002-5607-4901)
- Hong Chen (ORCID: https://orcid.org/0000-0003-3876-6514)
- Hao Jiang (ORCID: https://orcid.org/0000-0003-4123-4930)
- Madison Heady
Institutions
- Washington University in St. Louis (US)
- American Physical Therapy Association (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00881
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Parkinson Disease Association
- Paula and Rodger Riney Foundation
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke
- National Institute of Biomedical Imaging and Bioengineering