Considerable effort has previously been invested in a light‐controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene‐based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo‐controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light‐controlled tacrine‐based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis‐enriched form showed an 8.4‐fold higher inhibition of hAChE compared with its trans‐enriched form and was about 30‐fold more active than the reference compound tacrine with a single‐digit nanomolar inhibition. We went beyond proof‐of‐concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, “cis‐on” effect, and pronounces differences between the photoisomers.

Starting from multifunctional triazacyclononane-triphosphinate chelator cores, dendritic molecules with the ability to bind metal ions within their framework were synthesized. A cooperative interaction of the chelator cages resulted in a markedly increased affinity towards Ga. A hexameric PSMA inhibitor conjugate with high affinity (IC = 1.2 nM) and favorable in vivo PET imaging properties demonstrated practical applicability. The novel scaffolds are useful for synthesis of structurally well-defined multimodal imaging probes or theranostics.

Benzimidazole-based inhibitors of butyrylcholinesterase were designed and tested for their activity and selectivity in vitro, leading to compound (11d) that attenuated Aβ25-35-induced learning impairments in an Alzheimer's disease mouse model.

Purpose A neuropathological hallmark of Alzheimer’s disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with Aβ aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[18F]. IC50 values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman’s assay gave an IC50 value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K1 = 32.9 nM). Conclusions The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with 18F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.