Search

Background: The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [ 18 F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood-brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -d 4 and -d 8 deuterated isotopologues of [ 18 F]JHU94620., Results: The deuterated [ 18 F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with K D values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [ 18 F]JHU94620-d 8 in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats., Conclusion: These results support further investigations of [ 18 F]JHU94620-d 8 in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation., Competing Interests: Declarations. Ethics approval and consent to participate: All studies involving animals were carried out according to the national law on the protection of animals and were approved by the responsible authorities (Landesdirektion Sachsen, No. DD24.1-5131/446/19, TVV 18/18), CD-1 mice and Wistar rats were obtained from the Medizinisch-Experimentelles-Zentrum at Universität Leipzig (Leipzig, Germany) and a pig (German Landrace x German Large White) was obtained from the Lehr- und Versuchsgut Oberholz (Großpösna, Germany). Animals were kept under standard conditions with free access to water and food. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Glioma are clinically challenging tumors due to their location and invasiveness nature, which often hinder complete surgical resection. The evaluation of the isocitrate dehydrogenase mutation status has become crucial for effective patient stratification. Through a transdisciplinary approach, we have developed an 18 F-labeled ligand for non-invasive assessment of the IDH1R132H variant by using positron emission tomography (PET) imaging. In this study, we have successfully prepared diastereomerically pure [ 18 F]AG-120 by copper-mediated radiofluorination of the stannyl precursor 6 on a TRACERlab FX2 N radiosynthesis module. In vitro internalization studies demonstrated significantly higher uptake of [ 18 F]AG-120 in U251 human high-grade glioma cells with stable overexpression of mutant IDH1 (IDH1R132H) compared to their wild-type IDH1 counterpart (0.4 vs. 0.013% applied dose/µg protein at 120 min). In vivo studies conducted in mice, exhibited the excellent metabolic stability of [ 18 F]AG-120, with parent fractions of 85% and 91% in plasma and brain at 30 min p.i., respectively. Dynamic PET studies with [ 18 F]AG-120 in naïve mice and orthotopic glioma rat model reveal limited blood-brain barrier permeation along with a low uptake in the brain tumor. Interestingly, there was no significant difference in uptake between mutant IDH1R132H and wild-type IDH1 tumors (tumor-to-blood ratio [40-60 min] : ~1.7 vs. ~1.3). In conclusion, our preclinical evaluation demonstrated a target-specific internalization of [ 18 F]AG-120 in vitro, a high metabolic stability in vivo in mice, and a slightly higher accumulation of activity in IDH1R132H-glioma compared to IDH1-glioma. Overall, our findings contribute to advancing the field of molecular imaging and encourage the evaluation of [ 18 F]AG-120 to improve diagnosis and management of glioma and other IDH1R132H-related tumors., (© 2023. The Author(s).)

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 of 2.32 nM for the hCB2R vs 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.

This study describes the synthesis, radiofluorination and purification of an anionic amphiphilic teroligomer developed as a stabilizer for siRNA-loaded calcium phosphate nanoparticles (CaP-NPs). As the stabilizing amphiphile accumulates on nanoparticle surfaces, the fluorine-18-labeled polymer should enable to track the distribution of the CaP-NPs in brain tumors by positron emission tomography after application by convection-enhanced delivery. At first, an unmodified teroligomer was synthesized with a number average molecular weight of 4550 ± 20 Da by free radical polymerization of a defined composition of methoxy-PEG-monomethacrylate, tetradecyl acrylate and maleic anhydride. Subsequent derivatization of anhydrides with azido-TEG-amine provided an azido-functionalized polymer precursor ( o14PEGMA-N 3 ) for radiofluorination. The 18 F-labeling was accomplished through the copper-catalyzed cycloaddition of o14PEGMA-N 3 with diethylene glycol-alkyne-substituted heteroaromatic prosthetic group [ 18 F]2, which was synthesized with a radiochemical yield (RCY) of about 38% within 60 min using a radiosynthesis module. The 18 F-labeled polymer [ 18 F]fluoro-o14PEGMA was obtained after a short reaction time of 2-3 min by using CuSO 4 /sodium ascorbate at 90 °C. Purification was performed by solid-phase extraction on an anion-exchange cartridge followed by size-exclusion chromatography to obtain [ 18 F]fluoro-o14PEGMA with a high radiochemical purity and an RCY of about 15%.

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 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. 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 > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [ 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.

[ 18 F]FLUDA is a selective radiotracer for in vivo imaging of the adenosine A 2A receptor (A 2A R) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [ 18 F]FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [ 18 F]FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one-pot two-step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69-333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [ 18 F]FLUDA., (© 2022 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

The cerebral expression of the A 2A adenosine receptor (A 2A AR) is altered in neurodegenerative diseases such as Parkinson's (PD) and Huntington's (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A 2A AR-specific antagonist radiotracer [ 18 F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone-treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time-activity curves to calculate the mean residence time (MRT) by non-compartmental analysis, and the binding potential ( BP ND ) of [ 18 F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume ( V T ) at baseline and under blocking conditions with tozadenant. The MRT of [ 18 F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A 2A AR antagonist istradefylline. Mouse results showed the highest BP ND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A 2A AR availability in the rotenone-treated mice compared to the control-aged group. Tozadenant treatment significantly decreased the V T (14.6 vs. 8.5 mL · g -1 ) and BP ND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BP ND of [ 18 F]FLUDA in the striatum. We conclude that [ 18 F]FLUDA is a suitable tool for the non-invasive quantitation of altered A 2A AR expression in neurodegenerative diseases such as PD and HD, by PET.

A 2A adenosine receptors (A 2A -AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [ 18 F]FLUDA to non-invasively determine the A 2A -AR availability for diagnosis of the A 2A R status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A 2A -AR (A 2A -AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A 2A R ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters ( B max and   K D ) of [ 18 F]FLUDA on mouse and human atrial tissue samples by autoradiographic studies, and (3) investigated the in vivo uptake of the radiotracer by dynamic PET imaging in A 2A -AR TG and WT. After A 2A -AR stimulation by the A 2A -AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A 2A -AR-TG animals but not in WT. Radiolabelled [ 18 F]FLUDA exhibited a K D of 5.9 ± 1.6 nM and a B max of 455 ± 78 fmol/mg protein in cardiac samples of A 2A -AR TG, whereas in WT, as well as in human atrial preparations, only low specific binding was found. Dynamic PET studies revealed a significantly higher initial uptake of [ 18 F]FLUDA into the myocardium of A 2A -AR TG compared to WT. The hA 2A -AR-specific binding of [ 18 F]FLUDA in vivo was verified by pre-administration of the highly affine A 2A AR-specific antagonist istradefylline. Conclusion: [ 18 F]FLUDA is a promising PET probe for the non-invasive assessment of the A 2A -AR as a marker for pathologies linked to an increased A 2A -AR density in the heart, as shown in patients with heart failure.

The upregulation of the CB 2 receptors in neuroinflammation and cancer and their potential visualization with PET (positron emission tomography) could provide a valuable diagnostic and therapy-monitoring tool in such disorders. However, the availability of reliable CB 2 -selective imaging probes is still lacking in clinical practice. We have recently identified a benzothiazole-2-ylidine amide hit (6a) as a highly potent CB 2 ligand. With the aim of enhancing its CB 2 over CB 1 selectivity and introducing structural sites suitable for radiolabeling, we herein describe the development of fluorinated and methoxylated benzothiazole derivatives endowed with extremely high CB 2 binding affinity and an exclusive selectivity to the CB 2 receptor. Compounds 14, 15, 18, 19, 21, 24 and 25 displayed subnanomolar CB 2 K i values (ranging from 0.16 nM to 0.68 nM) and interestingly, all of the synthesized compounds completely lacked affinity at the CB 1 receptor (K i  > 10,000 nM for all compounds), indicating their remarkably high CB 2 over CB 1 selectivity factors. The fluorinated analogs, 15 and 21, were evaluated for their in vitro metabolic stability in mouse and human liver microsomes (MLM and HLM). Both 15 and 21 displayed an exceptionally high stability (98% and 91% intact compounds, respectively) after 60 min incubation with MLM. Contrastingly, a 5- and 2.8-fold lower stability was demonstrated for compounds 15 and 21, respectively, upon incubation with HLM for 60 min. Taken together, our data present extremely potent and selective CB 2 ligands as credible leads that can be further exploited for 18 F- or 11 C-radiolabeling and utilization as PET tracers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The adenosine A 2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A 2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A 2A receptor radiotracer and report herein the preclinical evaluation of [ 18 F]FLUDA, a deuterated isotopologue of [ 18 F]FESCH., Methods: [ 18 F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats., Results: [ 18 F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72-180 GBq/μmol. Autoradiography proved A 2A receptor-specific accumulation of [ 18 F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [ 18 F]FLUDA compared to that of [ 18 F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [ 18 F]FLUDA towards striatal A 2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [ 18 F]FLUDA., Conclusions: The new radiotracer [ 18 F]FLUDA is suitable to detect the availability of the A 2A receptor in the brain with high target specificity. It is regarded ready for human application.

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 F] PPY 1 and [18F] 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.

The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [ 18 F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [ 18 F]FACH in healthy mice and piglets. We measured the [ 18 F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [ 18 F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a K D of 118 ± 12 nM and B max of 6.0 pmol/mg wet weight. The specificity of [ 18 F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC 0-60min after pre-treatment with α-CCA-Na in mice (-47%) and in piglets (-66%). [ 18 F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [ 18 F]FACH binding potential (BP ND ) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [ 18 F]FACH uptake was confirmed by displacement studies in 4T1 cells. [ 18 F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.

The adenosine A 2A receptor (A 2A R) has emerged as a potential non-dopaminergic target for the treatment of Parkinson's disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A 2A R-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs ( TOZ1 - TOZ7 ) based on the structure of the A 2A R antagonist tozadenant , and the preclinical evaluation of [ 18 F] TOZ1 . Autoradiography proved A 2A R-specific in vitro binding of [ 18 F] TOZ1 to striatum of mouse and pig brain. Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no A 2A R-specific in vivo binding.

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 2B receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this receptor in pathological processes and most likely enable the identification and clinical monitoring of respective cancer therapies. On the basis of a bicyclic pyridopyrimidine-2,4-dione core structure, the new adenosine A 2B receptor ligand 9 was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound 9 showed a high binding affinity for the human A 2B receptor (K i (A 2B ) = 2.51 nM), along with high selectivities versus the A 1 , A 2A , and A 3 receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [ 18 F]F - /K 2.2.2. /K 2 CO 3 in DMSO at 120 °C. Metabolic studies of [ 18 F]9 in mice revealed about 60% of radiotracer intact in plasma at 30 minutes p.i. A preliminary PET study in healthy mice showed an overall biodistribution of [ 18 F]9 , corresponding to the known ubiquitous but low expression of the A 2B receptor. Consequently, [ 18 F]9 represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A 2B receptor and a suitable in vivo profile. Subsequent studies are envisaged to investigate the applicability of [ 18 F]9 to detect alterations in the receptor density in certain cancer-related disease models., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Overexpression of monocarboxylate transporters (MCTs) has been shown for a variety of human cancers (e.g., colon, brain, breast, and kidney) and inhibition resulted in intracellular lactate accumulation, acidosis, and cell death. Thus, MCTs are promising targets to investigate tumor cancer metabolism with positron emission tomography (PET). Here, the organ doses (ODs) and the effective dose (ED) of the first 18 F-labeled MCT1/MCT4 inhibitor were estimated in juvenile pigs. Whole-body dosimetry was performed in three piglets (age: ~6 weeks, weight: ~13-15 kg). The animals were anesthetized and subjected to sequential hybrid Positron Emission Tomography and Computed Tomography (PET/CT) up to 5 h after an intravenous (iv) injection of 156 ± 54 MBq [ 18 F]FACH. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity data. Time and mass scales were adapted to the human order of magnitude and the ODs calculated using the ICRP 89 adult male phantom with OLINDA 2.1. The ED was calculated using tissue weighting factors as published in Publication 103 of the International Commission of Radiation Protection (ICRP103). The highest organ dose was received by the urinary bladder (62.6 ± 28.9 µSv/MBq), followed by the gall bladder (50.4 ± 37.5 µSv/MBq) and the pancreas (30.5 ± 27.3 µSv/MBq). The highest contribution to the ED was by the urinary bladder (2.5 ± 1.1 µSv/MBq), followed by the red marrow (1.7 ± 0.3 µSv/MBq) and the stomach (1.3 ± 0.4 µSv/MBq). According to this preclinical analysis, the ED to humans is 12.4 µSv/MBq when applying the ICRP103 tissue weighting factors. Taking into account that preclinical dosimetry underestimates the dose to humans by up to 40%, the conversion factor applied for estimation of the ED to humans would rise to 20.6 µSv/MBq. In this case, the ED to humans upon an iv application of ~300 MBq [ 18 F]FACH would be about 6.2 mSv. This risk assessment encourages the translation of [ 18 F]FACH into clinical study phases and the further investigation of its potential as a clinical tool for cancer imaging with PET.

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.

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumour development and progression. Their level of expression is particularly upregulated in glycolytic cancer cells and accordingly MCTs are considered as promising drug targets for treatment of a variety of human cancers. The non-invasive imaging of these transporters in cancer patients via positron emission tomography (PET) is regarded to be valuable for the monitoring of therapeutic effects of MCT inhibitors. Recently, we developed the first 18 F-radiolabelled MCT1/MCT4 inhibitor [ 18 F]FACH and reported on a two-step one-pot radiosynthesis procedure. We herein describe now a unique one-step radiosynthesis of this radiotracer which is based on the approach of using a methylsulfonate (mesylate) precursor bearing an unprotected carboxylic acid function. With the new procedure unexpected high radiochemical yields of 43 ± 8% at the end of the radiosynthesis could be obtained in a strongly reduced total synthesis time. Moreover, the radiosynthesis was successfully transferred to a TRACERlab FX2 N synthesis module ready for future preclinical applications of [ 18 F]FACH.

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [ 18 F]FACH ((E)-2-cyano-3-{4-[(3-[ 18 F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[ 14 C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[ 18 F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[ 18 F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[ 18 F]F-K 2.2.2 -carbonate or [ 18 F]TBAF. The final deprotected product [ 18 F]FACH was only obtained when [ 18 F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [ 18 F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%)., (© 2019 John Wiley & Sons, Ltd.)

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 type 2 receptors (CB 2 receptors) are involved in various pathological processes, and the visualization of their in vivo availability with positron emission tomography (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB 2 receptor ligand N -(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1 H -imidazole-4-carboxamide ( 5 ). A novel series of compounds was developed by modifying (i) the adamantane-3-position, (ii) the imidazole- N -phenyl ring, and (iii) the imidazole-2-position, and the impact on the CB 2 binding affinity and selectivity toward cannabinoid type 1 receptors (CB 1 ) was evaluated. This study identified compound 15 as one of the most potent ( K i (CB 2 ) = 0.29 nM) and selective (CB 1 /CB 2 > 10000) CB 2 receptor ligands discovered so far, eligible for the development of an 18 F-labeled PET radiotracer.

The ghrelin receptor (GhrR) is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound ( S )-6-(4-bromo-2-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4(3 H )-one (( S )- 9 ) has been described as a GhrR ligand with high binding affinity. Here, we describe the synthesis of fluorinated derivatives, the in vitro evaluation of their potency as partial agonists and selectivity at GhrRs, and their physicochemical properties. These results identified compounds ( S )- 9 , ( R )- 9 , and ( S )- 16 as suitable parent molecules for 18 F-labeled positron emission tomography (PET) radiotracers to enable future investigation of GhrR in the brain.

A small series of indol-3-yl-oxoacetamides was synthesized starting from the literature known N -(adamantan-1-yl)-2-(5-(furan-2-yl)-1-pentyl-1 H -indol-3-yl)-2-oxoacetamide ( 5 ) by substituting the 1-pentyl-1 H -indole subunit. Our preliminary biological evaluation showed that the fluorinated derivative 8 is a potent and selective CB₂ ligand with K i = 6.2 nM.

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).

Reaction of pyrrole-2-carboxamides with Selectfluor in MeCN/water (4:1) affords 2-hydroxy-5-oxopyrrole-2-carboxamides in yields of up to 80 %. A variety of sensitive functional groups is tolerated, among them aldehydes and alkynes. The new method also works in the presence of allyl groups and appears to be superior to the use of singlet oxygen. Reaction of the monobrominated dihydropyrrolo[1,2-a]pyrazinone mukanadin C and its nonbrominated analogue afforded bicyclic hydroxypyrrolones. These compounds are interesting as they constitute a partial structure of the marine natural product oxocyclostylidol., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [18F]1 and [18F]2 as CB2 receptor PET imaging agents., Results: High binding affinity and specificity towards CB2 receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of 1 and 2. Aliphatic and aromatic radiofluorinations were optimized, and [18F]1 and [18F]2 were achieved in radiochemical yields of ≥30% with radiochemical purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood-brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [18F]1 and [18F]2 accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [18F]2 could be identified as the free acid [18F]10, which has no affinity towards the CB1 and CB2 receptors but can cross the BBB., Conclusions: N-aryl-oxadiazolyl-propionamides can successfully be radiolabelled with 18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promising in vitro behavior, a rather rapid peripheral metabolism of [18F]1 and [18F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [18F]1 and [18F]2 will help to elucidate the potential of this class of compounds for CB2R PET studies.