Novel application of [18F]DPA714 for visualizing the pulmonary inflammation process of SARS-CoV-2-infection in rhesus monkeys (Macaca mulatta)

RATIONALE: The aim of this study was to investigate the application of [18F]DPA714 to visualize the inflammation process in the lungs of SARS-CoV-2-infected rhesus monkeys, focusing on the presence of pulmonary lesions, activation of mediastinal lymph nodes and surrounded lung tissue. METHODS: Four experimentally SARS-CoV-2 infected rhesus monkeys were followed for seven weeks post infection (pi) with a weekly PET-CT using [18F]DPA714. Two PET images, 10 min each, of a single field-of-view covering the chest area, were obtained 10 and 30 min after injection. To determine the infection process swabs, blood and bronchoalveolar lavages (BALs) were obtained. RESULTS: All animals were positive for SARS-CoV-2 in both the swabs and BALs on multiple timepoints pi. The initial development of pulmonary lesions was already detected at the first scan, performed 2-days pi. PET revealed an increased tracer uptake in the pulmonary lesions and mediastinal lymph nodes of all animals from the first scan obtained after infection and onwards. However, also an increased uptake was detected in the lung tissue surrounding the lesions, which persisted until day 30 and then subsided by day 37-44 pi. In parallel, a similar pattern of increased expression of activation markers was observed on dendritic cells in blood. PRINCIPAL CONCLUSIONS: This study illustrates that [18F]DPA714 is a valuable radiotracer to visualize SARS-CoV-2-associated pulmonary inflammation, which coincided with activation of dendritic cells in blood. [18F]DPA714 thus has the potential to be of added value as diagnostic tracer for other viral respiratory infections

Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state

Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory/protective state of microglia for the development of novel PET tracers.Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues.Results: Here we provide evidence that P2RYI2 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-II labeled tracer targeting P2RYI2, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient.Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.</div

Recent Progress in Metal Catalyzed Direct Carboxylation of Aryl Halides and Pseudo Halides Employing CO2: Opportunities for 11C Radiochemistry

Carbon dioxide (CO) as a synthon in organic transformations is very useful, especially when combined with transition metal catalysts. CO insertion on carbon(Aryl)-metal is are an elegant route to construct carbon–carbon bonds. A limited number of reports have been published to date on the direct conversion of aryl halides (or pseudo halides) to aryl carboxylic acids using transition metal catalysts. These reactions place great demand on the choice of catalyst, starting material, and reducing agent. However, these approaches could be of interest for the synthesis of a wide range of biologically active small molecules. Such transformations have already been applied for the synthesis of radiolabeled compounds for imaging with positron emission tomography (PET) using cyclotron produced [C]CO and may be applicable to the production of a diverse range of PET tracers

Recent Progress in Metal Catalyzed Direct Carboxylation of Aryl Halides and Pseudo Halides Employing CO2: Opportunities for 11C radiochemistry

Carbon dioxide (CO2) as a synthon in organic transformations is very useful, especially when combined with transition metal catalysts. CO2 insertion on carbon(Aryl)-metal bonds are an elegant way to construct carbon-carbon bonds. A limited number of reports has been published to date on direct conversion of aryl halides (or pseudo halides) to aryl carboxylic acids using transition metal catalysts. These reactions place great demand on the choice of catalyst, starting material and reducing agent being used. However, these approaches could be of interest for the synthesis of a wide range of biologically active small molecules. Such transformations have already been applied for the synthesis of radiolabeled compounds for imaging with positron emission tomography (PET) using cyclotron produced [11C]CO2 and may be applicable to produce diverse range of PET tracers in the future.status: publishe

Radiosynthesis of 1-iodo-2-[11C]methylpropane and 2-methyl-1-[11C]propanol and its application for alkylation reactions and C―C bond formation

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1-iodo-2-[11C]methylpropane and 2-methyl-1-[11C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2-Methyl-1-[11C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 μmol) were needed. 1-Iodo-2-[11C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1-iodo-2-[11C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [11C]2-methyl-1-propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/μmol at the end of synthesis. Altogether, the syntheses of 1-iodo-2-[11C]methylpropane and 2-methyl-1-[11C]propanol were achieved and applied as proof of their applicability

Automation of the radiosynthesis and purification procedures for [18F]Fluspidine preparation, a new radiotracer for clinical investigations in PET imaging of σ1 receptors in brain

International audienceThe radiosynthesis of [18F]Fluspidine, a potent σ1 receptor imaging probe for pre-clinical/clinical studies, was implemented on a TRACERlabTM FX F-N synthesizer. [18F]2 was synthesized in 15 min at 85 °C starting from its tosylate precursor. Purification via semi-preparative RP-HPLC was investigated using different columns and eluent compositions and was most successful on a polar RP phase with acetonitrile/water buffered with NH4OAc. After solid phase extraction, [18F]Fluspidine was formulated and produced within 59 ± 4 min with an overall radiochemical yield of 37 ± 8%, a radiochemical purity of 99.3 ± 0.5% and high specific activity (176.6 ± 52.0 GBq/µmol)

Use of 3-[18F]fluoropropanesulfonyl chloride as a prosthetic agent for the radiolabelling of amines: Investigation of precursor molecules, labelling conditions and enzymatic stability of the corresponding sulfonamides

3-[18F]Fluoropropanesulfonyl chloride, a recently proposed prosthetic agent for fluorine-18 labelling, was prepared in a two-step radiosynthesis via 3-[18F]fluoropropyl thiocyanate as an intermediate. Two benzenesulfonate-based radiolabelling precursors were prepared by various routes. Comparing the reactivities of 3-thiocyanatopropyl nosylate and the corresponding tosylate towards [18F]fluoride the former proved to be superior accounting for labelling yields of up to 85%. Conditions for a reliable transformation of 3-[18F]fluoropropyl thiocyanate to the corresponding sulfonyl chloride with the potential for automation have been identified. The reaction of 3-[18F]fluoropropanesulfonyl chloride with eight different aliphatic and aromatic amines was investigated and the identity of the resulting 18F-labelled sulfonamides was confirmed chromatographically by comparison with their nonradioactive counterparts. Even for weakly nucleophilic amines such as 4-nitroaniline the desired radiolabelled sulfonamides were accessible in satisfactory yields owing to systematic variation of the reaction conditions. With respect to the application of the 18F-fluoropropansulfonyl group to the labelling of compounds relevant as imaging agents for positron emission tomography (PET), the stability of N-(4-fluorophenyl)-3-fluoropropanesulfonamide against degradation catalysed by carboxylesterase was investigated and compared to that of the analogous fluoroacetamide

Radiosynthesis of racemic and enantiomerically pure (-)-[18F]flubatine - A promising PET radiotracer for neuroimaging of alpha-4 beta-2 nicotinic acetylcholine receptors

(−)-[18F]flubatine is a promising agent for visualization by PET of cerebral α4β2 nicotinic acetylcholine receptors (nAChRs), which are implicated in psychiatric and neurodegenerative disorders. Here, we describe a substantially improved two-step radiosynthesis strategy for (−)-[18F]flubatine, based on the nucleophilic radiofluorination of an enantiomerically pure precursor followed by deprotection of the intermediate. An extensive leaving group/protecting group library of precursors was tested. Application of a trimethylammonium-iodide precursor with a Boc-protecting group provided the best results: labeling efficiencies of 80–95%, RCY of 60±5%, radiochemical purity of >98%, and a specific activity of >350 GBq/μmol. The radiosynthesis is easily transferable to an automated synthesis module

Radiosynthesis and Radiotracer Properties of a 7-(2-[18F]Fluoroethoxy)-6-methoxypyrrolidinylquinazoline for Imaging of Phosphodiesterase 10A with PET

International audienc