Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD.

Abstract

It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to Aβ-peptides and prevent Aβ aggregation. We have previously shown that treatment of Alzheimer's Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of 131I-labeled IDIF and 131I- and 124I-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher Aβ-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice.

• Authors: Xabier Rios, Vanessa Gómez-Vallejo, Abraham Martín, Unai Cossío, Miguel Ángel Morcillo, Mobina Alemi, Isabel Cardoso, Jordi Quintana, Jesús Jiménez-Barbero, Ellen Y Cotrina, Gregorio Valencia, Gemma Arsequell, Jordi Llop
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 13672 (09 20 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31541162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Iodine Radioisotopes
• Prealbumin
• iododiflunisal
• Diflunisal

Topics

• Administration, Intravenous
• Amyloid beta-Peptides (metabolism)
• Animals
• Autoradiography
• Blood-Brain Barrier (chemistry)
• Brain (diagnostic imaging, metabolism)
• Diflunisal (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics)
• Iodine Radioisotopes (chemistry)
• Mice
• Positron-Emission Tomography
• Prealbumin (administration & dosage, chemistry, pharmacokinetics)
• Tissue Distribution