Synthetic route for MBTHam.

<p>Synthetic route for MBTHam.</p

In vitro autoradiograms of human brain sections from a patient with CAA.

<p>The sections are labeled with [^99mTc]MBT2 (A) and [^99mTc]BT2B (C). The adjacent brain section is immunostained with an antibody against β-amyloid (B). ^aData from our previous study (Ref. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0163969#pone.0163969.ref028" target="_blank">28</a>).</p

Percent radiochemical purity of [^99mTc]MBT2 and [^99mTc]BT2 as a function of time.

<p>Percent radiochemical purity of [^99mTc]MBT2 and [^99mTc]BT2 as a function of time.</p

Radiochromatograms of [^99mTc]BT2 (A) and [^99mTc]MBT2 (B).

<p>Radiochromatograms of [^99mTc]BT2 (A) and [^99mTc]MBT2 (B).</p

Chemical structure of <i>N</i>-methyl-substituted [^99mTc]BT2 ([^99mTc]MBT2).

<p>Chemical structure of <i>N</i>-methyl-substituted [^99mTc]BT2 ([^99mTc]MBT2).</p

Half-maximal inhibitory concentration (IC₅₀, μM) for the binding of PIB to Aβ aggregates determined using ^99mTc-Ham complexes as ligands.

<p>Half-maximal inhibitory concentration (IC₅₀, μM) for the binding of PIB to Aβ aggregates determined using ^99mTc-Ham complexes as ligands.</p

In vitro autoradiograms of mouse brain sections labeled with ^99mTc-Ham complexes.

<p>The sections are from wild-type (A, E, and I) and Tg2576 (B, F, and J) mice. The same Tg2576 mouse brain sections are stained with thioflavin-S (C, G, and K). Blocking studies with PIB are also performed using the adjacent brain sections (D, H, and L). ^aData from our previous study (Ref. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0163969#pone.0163969.ref030" target="_blank">30</a>).</p

Enhancement of Binding Affinity for Amyloid Aggregates by Multivalent Interactions of ^99mTc-Hydroxamamide Complexes

Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel ^99mTc-hydroxamamide (^99mTc-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using β-amyloid peptide (Aβ(1–42)) aggregates as a model. In vitro inhibition assay indicated that bivalent ^99mTc-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using <i>Tg2576</i> mice showed the specific binding of bivalent ^99mTc-Ham complexes to Aβ plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent ^99mTc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates

Structure–Activity Relationship Study of Heterocyclic Phenylethenyl and Pyridinylethenyl Derivatives as Tau-Imaging Agents That Selectively Detect Neurofibrillary Tangles in Alzheimer’s Disease Brains

In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer’s disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)­ethenyl derivatives with or without a dimethyl amino group. In <i>in vitro</i> autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([¹²⁵I]<b>64</b>) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [¹²⁵I]<b>64</b> also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [¹²³I]<b>64</b> may be a new candidate tau-imaging agent

Ex vivo autoradiograms of brain sections after injection of [¹²³I]8 into a Tg2576 mouse (A) and a wild-type mouse (B).

<p>Fluorescent staining of the same brain section (A and B) with thioflavin S is shown in Figures C and D, respectively.</p