Divalent 2-(4-Hydroxyphenyl)benzothiazole Bifunctional Chelators for ⁶⁴Cu Positron Emission Tomography Imaging in Alzheimer’s Disease

Abstract

Herein, we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid β aggregates and favorable lipophilicity for blood−brain barrier penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity toward Cu(II). The novel BFCs form stable 64 Cu-radiolabeled complexes and exhibit promising partition coefficient (logD) values of 1.05−1.85. Among the five compounds tested, the 64 Cu-YW-15 complex exhibits significant staining of amyloid β plaques in ex vivo autoradiography studies. In addition, biodistribution studies show that 64 Cu-YW-15-Me exhibits moderate brain uptake (0.69 ± 0.08 %ID/g) in wild type mice.

Coordination Chemistry of Sulfur-Containing Bifunctional Chelators: Toward in Vivo Stabilization of 64Cu PET Imaging Agents for Alzheimer’s Disease

“…In our efforts to develop 64 Cu-based PET imaging agents for AD, we had primarily focused on the development of BFCs containing nitrogen-based macrocycles (TACN or N4). , However, due to their low affinity toward Cu­(I), these BFCs can potentially suffer from demetalation upon reduction in the reducing in vivo environment. Recently, our group has also investigated the applications of novel Pd­(I) complexes and Ni­(I) complexes supported by the dithiapyridinophane (N2S2) ligands in cross-coupling or hydrogen evolution reactions, indicating the superior stabilizing effect of the ligands toward low-valent metal centers. , Inspired by these results, we are encouraged to investigate the differences between the N2S2-based ligands and diazapyridinophane (N4) ligands on their chelating abilities toward both Cu­(II) and Cu­(I).…”

“…To achieve 64 Cu-based AD diagnosis, different strategies have been applied to develop bifunctional chelators (BFCs). Both macrocyclic and acyclic copper chelators, including a family of 1,4,7-triazacyclononane (TACN), 2,11-diaza[3.3]-(2,6)­pyridinophane (N4), and bis­(thiosemicarbazone) (ATSM) ligands, have been successfully attached to Aβ binding fragments (e.g., benzothiazole or stilbene derivatives) covalently. − Due to their strong copper chelating abilities and high specificity toward Aβ aggregates, these developed BFCs can be labeled with 64 Cu and are able to differentiate transgenic AD mice vs wild-type (WT) mice, suggesting their future usage in clinical studies.…”

A closer look at amyloid ligands, and what they tell us about protein aggregates

“…We compiled a database of 3457 measurements of ligand–amyloid fibril interactions from the scientific literature. 50–385 The requirements to be included in this database were (1) a known chemical structure, (2) a structure that does not contain metals (metalloligands have been thoroughly reviewed elsewhere in the literature 43,386–391 ), (3) a K d or IC 50 measurement, and (4) a fibril target related to Aβ, tau, or αSyn. Nearly half of the database reports on binding to Aβ fibrils formed in vitro , although recent years has seen a shift in focus toward tau and αSyn fibrils formed in vitro (Table 1).…”

Pentadentate and Hexadentate Pyridinophane Ligands Support Reversible Cu(II)/Cu(I) Redox Couples

“…Mononuclear copper complexes have been extensively utilized throughout various areas of inorganic chemistry: synthesis of structural or functional biomimetic inorganic complexes of Cu-containing enzymes [1][2][3][4], cation detection or sequestration [5,6], development of metal-based therapeutic or diagnostic compounds [7][8][9][10], and many others. In particular, the development of 64 Cu-based positron emission tomography (PET) agents has garnered significant attention in recent years as an alternative to shorter-lived radionuclides 11 C and 18 F, which are commonly used in PET imaging [11][12][13].…”