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Breast cancer resistance protein (BCRP, ABCG2) is an efflux transporter that plays a crucial role in multidrug resistance to antineoplastic drugs. Ko143, an analogue of the natural product fumitremorgin C, is a potent inhibitor of ABCG2 but is rapidly hydrolyzed to an inactive metabolite in vivo. To identify ABCG2 inhibitors with improved metabolic stability, we have assessed a series of Ko143 analogues for their ability to inhibit ABCG2-mediated transport in ABCG2-transduced MDCK II cells and determined the stability of the most potent compounds in liver microsomes. The most promising analogues were evaluated in vivoby positron emission tomography. In vitro, three of the tested analogues were potent ABCG2 inhibitors and stable in microsomes. In vivo, they increased the distribution of the ABCG2/ABCB1 substrate [11C]tariquidar to the brain both in wild-type (with Abcb1a/b transport blocked by tariquidar) and Abcb1a/b(−/−) mice. One analogue was more potent than Ko143 in both animal models.

Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. (R)-[18F]13was identified through the preliminary evaluation of two carbon-11-labeled racemic structures [11C]11and [11C]16. In dynamic positron-emission tomography (PET) scans, (R)-[18F]13showed a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain. High brain uptake and brain-to-blood ratio were achieved by (R)-[18F]13in comparison with previously reported reversible MAGL PET radiotracers. Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of (R)-[18F]13accumulation in the mouse brain. These findings indicate that (R)-[18F]13([18F]YH149) is a highly promising PET probe for visualizing MAGL non-invasively in vivoand holds great potential to support drug development.

The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Kifor CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6exhibited outstanding in vitroperformance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n= 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]RoSMA-18-d6showed exceptional CB2 attributes as demonstrated by in vitroautoradiography, ex vivobiodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d6was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d6is a promising CB2 PET radioligand for clinical translation.

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [11C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a Ki(hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [18F]3was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [18F]3to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [18F]3in the rat brain. [18F]3detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [18F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [18F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [18F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

Cannabinoid receptor CB2(CB2R) is upregulated on activated microglia and astrocytes in the brain under inflammatory conditions and plays important roles in many neurological diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and ischemic stroke. The advent of positron emission tomography (PET) using CB2R radiotracers has enabled the visualization of CB2R distribution in vivo in animal models of central nervous system inflammation, however translation to humans has been less successful. Several novel CB2R radiotracers have been developed and evaluated to quantify microglial activation. In this review, we summarize the recent preclinical and clinical imaging results of CB2R PET tracers and discuss the prospects of CB2R imaging using PET.

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure–affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [11C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [11C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

As a continuation of our research efforts toward the development of tryptophan-based radiotracers for tumor imaging with positron emission tomography (PET), three new fluoroethoxy tryptophan analogues were synthesized and evaluated in vivo. These new tracers (namely, 4-(2-[18F]fluoroethoxy)-dl-tryptophan ([18F]4-FEHTP), 6-(2-[18F]fluoroethoxy)-dl-tryptophan ([18F]6-FEHTP), and 7-(2-[18F]fluoroethoxy)-dl-tryptophan ([18F]7-FEHTP) carry the fluoroethoxy side chain either at positions 4-, 6-, or 7- of the indole core. Reference compounds and precursors were synthesized by multistep approaches. Radiosynthesis was accomplished by no-carrier-added nucleophilic 18F-fluorination following either an indirect approach (O-alkylation of the corresponding hydroxytryptophan with [18F]fluoroethyltosylate) or a direct approach (nucleophilic [18F] fluorination using a protected mesyl precursor). Radiochemical yields (decay corrected) for both methods were in the range of 10–18%. Small animal PET imaging with xenograft-bearing mice revealed the highest tumor/background ratio for [18F]6-FEHTP which, in a direct comparison, outperformed the other two tryptophan tracers and also the well-established tyrosine analogue O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]l-FET). Investigation of the transport mechanism of [18F]6-FEHTP in small cell lung cancer cells (NCI-H69) revealed that it is most probably taken up exclusively via the large neutral amino acid transporter(s) (LAT).

A new method for the 18F‐radiolabeling of aromatic compounds based on the aromatic nucleophilic substitution (SNAr) reaction using triarylsulfonium salts has been developed. Experiments and DFT calculations indicated that sulfonium ions have the potential to be optimized for labeling nonactivated and deactivated aryl rings that have Hammett σPsubstituent constants greater than –0.170. This method is applicable to a range of halogen‐substituted aryl systems including nonactivated and deactivated aryl rings. In particular, the high radiochemical yield of [18F]‐4‐fluoroiodobenzene from precursor 1arepresents a ready source of compound 1bfor subsequent use in palladium‐catalyzed C–H activation/C–C bond‐forming reactions.

Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCR), which activate intracellular secondary messenger systems when bound by the physiological ligand glutamate. Modulation of mGluR5s has potential for the treatment of variety of psychiatric and neurological diseases such as depression, anxiety, schizophrenia and Parkinsons disease. Positron emission tomography (PET) might offer the possibility to visualize the mGluR5 and present an interesting tool for studying this receptor-subtype under physiologic and pathologic conditions. In this review paper, emphasis is given to the radiosynthesis, in vitro and in vivo characterization of recently published mGluR5 PET tracers.

Water stable!Radiochemists have recently discovered silicon chemistry as a tool for the introduction of 18F into biomolecules for positron emission tomography (PET) imaging. 18F‐labeled PET tracers must be stable towards defluorination under physiological conditions. Here, a theoretical model of organofluorosilane hydrolysis is developed that correlates with the experimentally determined hydrolytic half‐lives and allows estimation of the stability of newly designed compounds (see scheme).

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The crystal structure of the resting state of cytochrome P450cam (CYP101), a heme thiolate protein, shows a cluster of six water molecules in the substrate binding pocket, one of which is coordinating to iron(III) as sixth ligand. The resting state is low-spin and changes to high-spin when substrate camphor binds and H2O is removed. In contrast to the protein, previously synthesised enzyme models such as H2O&bond;FeIII(porph)(ArS−) were shown to be purely high-spin. Iron(S−)porphyrins with different distal sites mimicking proposed remote effects have been prepared and studied by cw-EPR. The results indicate that the low-spin of the resting state of P450cam is due to the fact that the water molecule coordinating to iron has an OH−-like character because of hydrogen bonding and polarisation of the water cluster, respectively.

The crystal structure of the resting state of cytochrome P450cam (CYP101), a heme thiolate protein, shows a cluster of six water molecules in the substrate binding pocket, one of which is coordinating to iron(III) as sixth ligand. The resting state is low-spin and changes to high-spin when substrate camphor binds and H2O is removed. In contrast to the protein, previously synthesised enzyme models such as H2O&bond;Fe^III(porph)(ArS⁻) were shown to be purely high-spin. Iron(S⁻)porphyrins with different distal sites mimicking proposed remote effects have been prepared and studied by cw-EPR. The results indicate that the low-spin of the resting state of P450cam is due to the fact that the water molecule coordinating to iron has an OH⁻-like character because of hydrogen bonding and polarisation of the water cluster, respectively.

AbstractA series of cyclic peptides which contain benzene and cystine were synthesized by one-pot method. These compounds are found to selectively bind Ca2+and Eu3+cations and can also serve as good receptors for disodium 4-nitrophenyl phosphate anion.

AbstractThe reduction of manganese(III) porphyrins by hydrazine (L) was investigated by stopped-flow techniques. The mechanism of the reaction has been proposed based on the experimental results; the relationship between pseudo-first-order rate constants with the concentration of L. Calculated activation parameters showed that the pre-equilibrium step was exothermic and the reduction step endothermic. Substituent effects in the phenyl rings on the two steps have been examined.

A convenient procedure for the preparation of 1-aryl-3,3-dialkylureas using bis(trichoromethyl) carbonate (`triphosgene') is described.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.