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.

Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer’s Disease

“…In a revealing experiment, and using an AD transgenic mouse model with TTR genetic reduction (AD/TTR+/-), it was reported that IDIF administration resulted in decreased amyloid burden and total Aβ brain levels, and in the improved cognitive function of the animals [102]. Importantly, recent data showed that the TTR/IDIF complex exhibits improved BBB permeability, as compared to TTR and IDIF alone [103], providing higher Aβ sequestering capacity, and adding to the therapeutic potential of TTR in AD. In a different work, administration of resveratrol, to the AD/TTR+/-mouse model, also produced decreased brain Aβ burden and raised plasma TTR concentrations [104], confirming the stabilization hypothesis, whereas administration of resveratrol to a different AD mouse model, although not inducing decreased plaque burden, increased TTR protein concentration in the brain [105].…”

Oral treatment with iododiflunisal delays beta amyloid plaque formation in a transgenic mouse model of Alzheimer Disease: a Longitudinal in vivo molecular imaging study

“…This is not surprising, since some studies show differences in the amount of TTR in different brain regions(58).Furthermore, our recent PET-imaging study shows that entrance of TTR into the brain after intravenous administration starts at the third ventricles, which suggests that TTR traffic occurs partially via the cerebrospinal fluid-brain barrier (CSFBB) and not only through the blood brain barrier (BBB)(37). Ultimately, this led to lower and delayed TTR presence in peripheral areas of the brain(37), such as CTX, where a significant concentration of TTR could be observed only at 6 hours after administration. Assuming the same transport mechanism of IDIF-and tolcapone-stabilized TTR this delay could be one of the reasons for insufficient influx of the complex into CTX.…”

“…One of these compounds, iododiflunisal (IDIF; Figure 1) has proven efficient in promoting Aβ clearance from the brain and improving animal's cognitive functions when orally administered to AD transgenic mice (AβPPswe/PS1A246E/TTR+/-) daily for 2 months, starting just before the onset of the disease (36). Another study showed that the formation of TTR-IDIF complex enhances brain penetration of both TTR and IDIF (37).…”

Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

“…Among known TTR mutants, the V30M [7] and the Y78F [8] are the most common FAP mutation and the most amyloidogenic, respectively. Moreover, the importance of TTR stability also concerns neurodegenerative disorders such as Parkinson's and Alzheimer's diseases [9,10].…”

“…Over time, a large number of SAR studies have been published in order to identify typical substructures which are shared by compounds that stabilize TTR tetramer [3,[34][35][36][37][38][39]. In this field, the potential of iodine as substituent (iodination hypothesis) has been intensively explored through evaluating the inhibition ability of iodinated compounds with respect to non-iodinated analogues [10,11,17,36,[40][41][42][43]. Among iodinated motifs, 2,4,6-triiodophenol proved to be one of the most potent TTR fibrillogenesis inhibitor known so far [11], and iododiflunisal was shown to stabilize TTR [17].…”