Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported.

A strategy utilizing a recyclable macrocycle transporter for the efficient synthesis of a triazolium-based [2]rotaxane.

A general synthesis of triazolium-containing [2]rotaxanes, which could not be accessed by other methods, is reported. It is based on a sequential strategy starting from a well-designed macrocycle transporter which contains a template for dibenzo-24-crown-8 and a N-hydroxysuccinimide (NHS) moiety. The sequence is: 1) synthesis by slippage of a [2]rotaxane building-block; 2) its elongation at its NHS end; 3) the delivery of the macrocycle to the elongated part of the axle by an induced translational motion; 4) the contraction process to yield the targeted [2]rotaxane and recycle the initial transporter.

A selective and sensitive near-infrared fluorescent probe for acetylcholinesterase imaging.

Two near infra-red (NIR) fluorescent probes HupNIR1 and HupNIR2 based on the huprine scaffold and cyanine 5.0 dye have been synthesised and evaluated in situ for the detection of acetylcholinesterases in different tissues. As anticipated by the initial properties of huprine, both probes displayed a high affinity and selectivity for AChE toward BChE, with IC50 values in the nanomolar range and without any non-specific binding in the tissues. HupNIR2 appears the best probe for AChE with a great selectivity and sensitivity for AChE even in the brain region displaying a low AChE concentration as striatum. Moreover, the binding of HupNIR2 is affected when AChE is inhibited with toxic molecules such as organophosphates. This work provides a new tool to visualize active AChE in biological applications.

PET and SPECT Radiotracers for Alzheimer's Disease.

The two main pathological hallmarks of Alzheimer's disease (AD) in the brain are senile plaques (SPs) composed of beta-amyloid (Aß) peptides and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. These hallmarks are associated with a cholinergic deficit. While the process leading to the development of AD is complex and multifactorial, and the etiology of AD is not completely known, it is nowadays clear that AD is a multifaceted illness requiring the combination of synergetic treatment strategies. Because definite diagnosis is achieved by postmortem examination of the brain, new noninvasive diagnostic imaging modalities for AD are in high demand, both to detect and monitor the evolution of this sickness, and evaluate the efficacy of treatments. Positron Emission Tomography (PET) is a nuclear molecular imaging technique that uses radiopharmaceuticals labeled with a positron-emitting isotope (carbon-11, fluorine-18, copper-64, gallium- 68…), to visualize in vivo cellular metabolism with high-spatial resolution and unique sensitivity, while Single-Photon Emission Computed Tomography (SPECT) using radioisotopes such as technetium-99m or iodine-123. Besides being a powerful tool for diagnosis (mostly in oncology with [(18)F]-FDG), PET experiments can provide information about biochemical mechanisms in living tissues or interactions between neurotransmitter and brain receptors. For the past two decades, numerous radiopharmaceuticals have been developed for imaging the lesions observed in AD patients. Tau aggregates and Aß plaques can also be visualized and quantified by mean of specific radioligands. The latter has been the focus of intense research efforts lately, leading to new FDA approved radiopharmaceuticals. This paper aimed at summarizing the recent advances in PET and SPECT imaging of AD pathophysiology.