Alzheimer's disease (AD) is pathologically characterized by the accumulation of β-amyloid (Aβ) deposits in the parenchymal and cortical brain. In this work, we designed, synthesized, and evaluated a series of near-infrared (NIR) probes with electron donor-acceptor end groups interacting through a π-conjugated system for the detection of Aβ deposits in the brain. Among these probes, 3b and 3c had excellent fluorescent properties (emission maxima > 650 nm and high quantum yields) and displayed high sensitivity and high affinities to Aβ aggregates (3b, Kd = 8.8 nM; 3c, Kd = 1.9 nM). Both 3b and 3c could readily penetrate the blood-brain barrier with high initial brain uptake and fast to moderate washout from the brain. In vivo NIR imaging revealed that 3b and 3c could efficiently differentiate transgenic and wild-type mice. In summary, our research provides new hints for developing smarter and more activatable NIR probes targeting Aβ.

A novel class of near-infrared molecules based on the donor-acceptor architecture were synthesized and evaluated as Aβ imaging probes. In vivo imaging studies suggested that MCAAD-3 could penetrate the blood-brain barrier and label Aβ plaques in the brains of transgenic mice. Computational studies could reproduce the experimental trends well.

The formation of extracellular amyloid-β (Aβ) plaques is a common molecular change that underlies several debilitating human conditions, including Alzheimer's disease (AD); however, the existing near-infrared (NIR) fluorescent probes for the in vivo detection of Aβ plaques are limited by undesirable fluorescent properties and poor brain kinetics. In this work, we designed, synthesized, and evaluated a new family of efficient NIR probes that target Aβ plaques by incorporating hydroxyethyl groups into the ligand structure. Among these probes, DANIR 8c showed excellent fluorescent properties with an emission maximum above 670 nm upon binding to Aβ aggregates and also displayed a high sensitivity (a 629-fold increase in fluorescence intensity) and affinity (Kd = 14.5 nM). Because of the improved hydrophilicity that was induced by hydroxyls, 8c displayed increased initial brain uptake and a fast washout from the brain, as well as an acceptable biostability in the brain. In vivo NIR fluorescent imaging revealed that 8c could efficiently distinguish between AD transgenic model mice and normal controls. Overall, 8c is an efficient and veritable NIR fluorescent probe for the in vivo detection of Aβ plaques in the brain.

Despite achievements in Aβ imaging, there is still a need to develop innovative compounds with selectivity and high affinity to Aβ. Positron emission tomography imaging agents will still be the trend in the field in the short term. Due to the low costs for single-photon emission computed tomography (SPECT) and the excellent nuclear properties of (99m)Tc, substantial research should be conducted on the development of the probes for SPECT. Refining the current imaging techniques and in the meantime developing new efficient imaging multimodality and compounds would be a promising approach to imaging Aβ.

Treatment of 8-NH 2 -BODIPY, 1 a, (BODIPY = boron,methyl]-1H-pyrrolato-kN]-) with NaH, followed by addition of acylchlorides, R.-C(= O)Cl, R = CH 3 , CH 2 Cl, Ph, produces the corresponding 8-amido-BODIPYs, RC(= O)NH-BODIPYs in good yield, R = Me, 2 (62 %); ClCH 2 , 3 (52 %); Ph, 4 (74 %). Structural and spectroscopic analyses indicate a lack of N-lone pair delocalization to the BODIPY core (normally exhibited by the parent 8-amino-BODIPYs) as a result of the BODIPY-NH + = CR-O À contribution to the amide structure. The new materials 2, 3, and 4 exhibit C8-N bond lengths significantly longer than the those in related 8-amino-BODIPYs, average 1.407 Å vs 1.327 Å; and the N-Cacyl bond lengths in the region associated with regular amides, average 1.38 Å. This lack of 8-N-BODIPY pi interaction results in a significant bathochromic shift in the absorbance spectra (modelled by empirically corrected Time Dependent-Density Functional Theory (TD-DFT) calculations) and removes the well-established blue emission for 8-amino-BODIPYs and the new materials revert to the "normal" green emission generally noted for 8substituted-BODIPYs.[a] L. Figure 1. (a) 8-R-BODIPYs; (b) 8-NHR-BODIPY illustrating hemicyanin resonance contribution B, R = H (1 a); iPr (1 b); iBu (1 c).ChemistrySelect Full Papers % 1 b 406 462 16 % 1 c 406 450 26 % ChemistrySelect Full Papers