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

• Published in: Scientific reports Vol. 9; no. 1; pp. 13672 - 11
• Main Authors: Rios, Xabier, Gómez-Vallejo, Vanessa, Martín, Abraham, Cossío, Unai, Morcillo, Miguel Ángel, Alemi, Mobina, Cardoso, Isabel, Quintana, Jordi, Jiménez-Barbero, Jesús, Cotrina, Ellen Y., Valencia, Gregorio, Arsequell, Gemma, Llop, Jordi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-09-2019; Nature Publishing Group
• Subjects: 59; 59/78; 631/378/1341; 631/92/612; 64/60; Administration, Intravenous; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloidogenesis; Animals; Autoradiography; Biodistribution; Blood-brain barrier; Blood-Brain Barrier - chemistry; Brain - diagnostic imaging; Brain - metabolism; Cerebrospinal fluid; Diflunisal - administration & dosage; Diflunisal - analogs & derivatives; Diflunisal - chemistry; Diflunisal - pharmacokinetics; Humanities and Social Sciences; Intravenous administration; Investigations; Iodine; Iodine Radioisotopes - chemistry; Low density lipoprotein receptors; Membrane permeability; Mice; multidisciplinary; Peptides; Permeability; Pharmacokinetics; Positron-Emission Tomography; Prealbumin - administration & dosage; Prealbumin - chemistry; Prealbumin - pharmacokinetics; Protein transport; Proteins; Science; Science (multidisciplinary); Thyroid gland; Tissue Distribution; Transthyretin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-50071-w

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
131
I-labeled IDIF and
131
I- and
124
I-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.