Smart D-π-A Type Near-Infrared Aβ Probes: Effects of a Marked π Bridge on Optical and Biological Properties

Abstract

To expand the scope of D-π-A based near-infrared (NIR) probes for detecting β-amyloid (Aβ) plaques and to systematically explore the relationship among their structural characteristics, optical properties, and biological properties, three series of smart NIR probes with different aromatic rings and up to seven trans double bonds were synthesized and evaluated. Marked correlations between the conjugated π system and properties of these probes, such as optical data, binding ability, and brain uptake, were observed. One probe, PHC-4, displayed improved properties as a NIR probe for the in vivo detection of Aβ plaques.

Theoretical Development of Near‐Infrared Bioluminescent Systems

“…It is found that the introduction of a conjugated double bond (π bridge) between the donor and accepter moieties contributes to redshifted light . The conjugated length of such a D –π–A system is one of the key factors affecting the optical (e.g., BL wavelength) and biological (e.g., binding affinity) properties . One luciferin analogue, which introduces a conjugated double bond between the M and N moieties, is synthesized and emits bright far‐red‐shifted light .…”

“…[23c] The conjugated length of such a Dp-A system is one of the key factors affecting the optical (e.g., BL wavelength) and biological (e.g.,b inding affinity) properties. [50] One luciferin analogue,w hich introduces ac onjugated double bond between the Ma nd Nm oieties, is synthesized and emits bright far-red-shifted light. [8] The corresponding oLu analogue (in category B)i si nvestigated theoretically.T wo cis (cis-u and cis-d)a nd two trans (trans-p and trans-c)c onformers of this analogue are presented in Figure 1.…”

Synthesis, crystal structure studies and solvatochromic behaviour of two 2-{5-[4-(dimethylamino)phenyl]penta-2,4-dien-1-ylidene}malononitrile derivatives

“…The optical and biological properties of NIR probes for the identification of -amyloids have been evaluated experimentally by different research groups (Zhou et al, 2017;Peccati et al, 2016;Kim et al, 2015;Cui, 2014;Peccati et al, 2017;Murugan et al, 2014). Fluorescent-based and multi-photon microscopy-based imaging techniques were used for -amyloid identification.…”

Structure–Property Relationships of Polyethylene Glycol Modified Fluorophore as Near-Infrared Aβ Imaging Probes

“…More recently, we expanded the scope of these Dπ-A probes and systemically elucidated the relationships between π-conjugated system (different lengths of polyenic chains and aromatic rings) and properties (optical and biological). 31 Polyethylene glycol (PEG) chains are connected by repeated units of ethylene glycol monomer and demonstrated favorable function on pharmacokinetic and pharmacodynamic in polypeptide drugs. 32 Since 2005, Zhang et al reported the conjugation of short PEG chains to Aβ homing ligands with a terminal fluorine-18 atom and achieved simple adjustment of the ligand lipophilicity and better in vivo pharmacokinetics.…”

“…Naphthyl aldehydes with different lengths of polyenic chains were obtained by iterative Wittig reaction following the similar methods reported previously. 31 The PEG modified acceptors (1−6) were produced by esterification from 2-cyanoacetate acid and short PEG chains (n = 1−3) with hydroxyl and methoxyl terminals, dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP) were employed as dehydrant and catalyst, respectively. The final NIR probes (7a−7c to 13a−13c) were readily synthesized using Knoevengel condensation between appropriate naphthyl aldehydes and PEG modified cyanoacetate substrates catalyzed by small amount of piperdine.…”