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The development of cannabinoid receptor type 2 (CB2R) PET radioligands has been intensively explored due to the pronounced CB2R upregulation under various pathological conditions. Herein, we report on the synthesis of a series of CB2R affine fluorinated indole-2-carboxamide ligands. Compound RM365 was selected for PET radiotracer development due to its high CB2R affinity ( K i = 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitro evaluation of [ 18 F]RM365 indicated species differences in the binding to CB2R ( K D F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [ K D > 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [ 18 F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [ 18 F]RM365 to reach and selectively label the hCB2R(D80N) with a high signal-to-background ratio. Thus, [ 18 F]RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.

The development of cannabinoid receptor type 2 (CB 2 R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB 2 R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB 2 R ligands. All tested compounds showed low nanomolar CB 2 R affinity, with ( Z )- N -[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3 H )-ylidene]-(1,7-dicarba- closo -dodecaboranyl)-carboxamide ( LUZ5 ) exhibiting the highest affinity (0.8 nM). Compound [ 18 F]LUZ5- d 8 . PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB In vivo evaluation revealed the improved metabolic stability of [ 18 F]LUZ5- d 8 compared to that of [ 18 F]JHU94620 . PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB 2 R ligands and gaining access to a new class of high-affinity CB 2 R ligands, while the in vivo pharmacology still needs to be addressed.

The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel 18 F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 ( LU13 ) was identified with the highest binding affinity and selectivity versus CB1R (CB2R K i = 0.6 nM; CB1R K i /CB2R K i is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.[ 18 F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [ 18 F]LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [ 18 F]LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis -[ 18 F]1-(4-fluorobutyl- N -((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([ 18 F] LU14 ) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [ 18 F] LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

The σ 2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ 2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ 2 receptor ligands motivates the research in the field of σ 2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1 H -indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1 H -pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18 F and evaluation regarding detection of σ 2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [ 18 F] RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ 2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ 2 receptor ligand [ 18 F] RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ 2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.

The adenosine A 2A receptor (A 2A R) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A 2A R-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound ( PPY ). Among those, the highly affine 4-fluorobenzyl derivate ( PPY1 ; K i ( h A 2A R) = 5.3 nM) and the 2-fluorobenzyl derivate ( PPY2 ; K i ( h A 2A R) = 2.1 nM) were chosen for 18 F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [ 18 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [ PPY 1 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [ 18 F] PPY 2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [ 18 F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [ 18 F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [ 14 C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC 50 = 11 nM) by factors of 11 and 25, respectively, 1 (IC 50 = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [ 18 F] 1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D 7.4 result for [ 18 F] 1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [ 18 F] 1 compared to [ 18 F]FACH, the in vivo brain uptake of [ 18 F] 1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.

The adenosine A 2A receptor (A 2A R) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson's disease (PD). An increased A 2A R availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A 2A R upregulation in PD. For that purpose, we selected the known A 2A R-specific radiotracer [ 18 F] FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [ 18 F] FESCH in the mouse striatum. Concomitantly, metabolism studies with [ 18 F] FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A 2A R binding of [ 18 F] FESCH was found. Nonetheless, the correlation between the increased A 2A R levels within the proposed PD animal model remains to be further investigated.

Purine nucleotides such as ATP and ADP are important extracellular signaling molecules in almost all tissues activating various subtypes of purinoreceptors. In the brain, the P2Y 1 receptor (P2Y 1 R) subtype mediates trophic functions like differentiation and proliferation, and modulates fast synaptic transmission, both suggested to be affected in diseases of the central nervous system. Research on P2Y 1 R is limited because suitable brain-penetrating P2Y 1 R-selective tracers are not yet available. Here, we describe the first efforts to develop an 18 F-labeled PET tracer based on the structure of the highly affine and selective, non-nucleotidic P2Y 1 R allosteric modulator 1-(2-[2-(tert-butyl)phenoxy]pyridin-3-yl)-3-[4-(trifluoromethoxy)phenyl]urea (7). A small series of fluorinated compounds was developed by systematic modification of the p-(trifluoromethoxy)phenyl, the urea and the 2-pyridyl subunits of the lead compound 7. Additionally, the p-(trifluoromethoxy)phenyl subunit was substituted by carborane, a boron-rich cluster with potential applicability in boron neutron capture therapy (BNCT). By functional assays, the new fluorinated derivative 1-{2-[2-(tert-butyl)phenoxy]pyridin-3-yl}-3-[4-(2-fluoroethyl)phenyl]urea (18) was identified with a high P2Y 1 R antagonistic potency (IC 50  = 10 nM). Compound [ 18 F]18 was radiosynthesized by using tetra-n-butyl ammonium [ 18 F]fluoride with high radiochemical purity, radiochemical yield and molar activities. Investigation of brain homogenates using hydrophilic interaction chromatography (HILIC) revealed [ 18 F]fluoride as major radiometabolite. Although [ 18 F]18 showed fast in vivo metabolization, the high potency and unique allosteric binding mode makes this class of compounds interesting for further optimizations and investigation of the theranostic potential as PET tracer and BNCT agent., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [(11)C](Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([(11)C]A-836339, [(11)C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [(18)F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [(18)F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [(11)C]1. In the LPS-treated mice, a 20-30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05).