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Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease
Joshi, S.M.; Wilson, T.C.; Li, Z.; Preshlock, S.; Gómez-Vallejo, V.; Gouverneur, V.; Llop, J.; Arsequell, G. Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease. Molecules2024, 29, 488.
Joshi, S.M.; Wilson, T.C.; Li, Z.; Preshlock, S.; Gómez-Vallejo, V.; Gouverneur, V.; Llop, J.; Arsequell, G. Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease. Molecules 2024, 29, 488.
Joshi, S.M.; Wilson, T.C.; Li, Z.; Preshlock, S.; Gómez-Vallejo, V.; Gouverneur, V.; Llop, J.; Arsequell, G. Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease. Molecules2024, 29, 488.
Joshi, S.M.; Wilson, T.C.; Li, Z.; Preshlock, S.; Gómez-Vallejo, V.; Gouverneur, V.; Llop, J.; Arsequell, G. Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease. Molecules 2024, 29, 488.
Abstract
The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer’s Disease (AD)-like pathology in mice, although mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/ 18F]exchange reaction over IDIF in dimethylsulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7±3% radiochemical yield in a 20 minutes reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t>10 min post administration), rapid accumulation in the liver, long circulation time and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.
Keywords
Iododiflunisal; transthyretin tetramer stabilizer; small-molecule chaperone; amyloid beta; in vivo imaging; 18F; positron emission tomography (PET).
Subject
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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