[18F]MK-7246 for Positron Emission Tomography Imaging of the Beta-Cell Surface Marker GPR44.

The progressive loss of beta-cell mass is a hallmark of diabetes and has been suggested as a complementary approach to studying the progression of diabetes in contrast to the beta-cell function. Non-invasive nuclear medicinal imaging techniques such as Positron Emission Tomography using radiation emitting tracers have thus been suggested as more viable methodologies to visualize and quantify the beta-cell mass with sufficient sensitivity. The transmembrane G protein-coupled receptor GPR44 has been identified as a biomarker for monitoring beta-cell mass. MK-7246 is a GPR44 antagonist that selectively binds to GPR44 with high affinity and good pharmacokinetic properties. Here, we present the synthesis of MK-7246, radiolabeled with the positron emitter fluorine-18 for preclinical evaluation using cell lines, mice, rats and human pancreatic cells. Here, we have described a synthesis and radiolabeling method for producing [18F]MK-7246 and its precursor compound. Preclinical assessments demonstrated the strong affinity and selectivity of [18F]MK-7246 towards GPR44. Additionally, [18F]MK-7246 exhibited excellent metabolic stability, a fast clearance profile from blood and tissues, qualifying it as a promising radioactive probe for GPR44-directed PET imaging.

MicroPET imaging of bacterial infection with nitroreductase-specific responsive 18F-labelled nitrogen mustard analogues.

PURPOSE: Bacterial infection and antibiotic resistance are serious threats to human health. This study aimed to develop two novel radiotracers, 18F-NTRP and 18F-NCRP, that possess a specific nitroreductase (NTR) response to image deep-seated bacterial infections using positron emission tomography (PET). This method can distinguish infection from sterile inflammation. METHODS: 18F-NTRP and 18F-NCRP were synthesized via a one-step method; all the steps usually involved in tracer radiosynthesis were successfully adapted in the All-In-One automated module. After the physiochemical properties of 18F-NTRP and 18F-NCRP were characterized, their specificity and selectivity for NTR were verified in E. coli and S. aureus. The ex vivo biodistribution of the tracers was evaluated in normal mice. MicroPET-CT imaging was performed in mouse models of bacterial infection and inflammation after the administration of 18F-NTRP or 18F-NCRP. RESULTS: Fully automated radiosynthesis of 18F-NTRP and 18F-NCRP was achieved within 90-110 min with overall decay-uncorrected, isolated radiochemical yields of 21.24 ± 4.25% and 11.3 ± 3.78%, respectively. The molar activities of 18F-NTRP and 18F-NCRP were 320 ± 40 GBq/µmol and 275 ± 33 GBq/µmol, respectively. In addition, 18F-NTRP and 18F-NCRP exhibited high selectivity and specificity for NTR response. PET-CT imaging in bacteria-infected mouse models with 18F-NTRP or 18F-NCRP showed significant radioactivity uptake in either E. coli- or S. aureus-infected muscles. The uptake for E. coli-infected muscles, 2.4 ± 0.2%ID/g with 18F-NTRP and 4.05 ± 0.49%ID/g with 18F-NCRP, was up to three times greater than that for uninfected control muscles. Furthermore, for both 18F-NTRP and 18F-NCRP, the uptake in bacterial infection was 2.6 times higher than that in sterile inflammation, allowing an effective distinction of infection from inflammation. CONCLUSION: 18F-NTRP and 18F-NCRP are worth further investigation to verify their potential clinical application for distinguishing bacterial infection from sterile inflammation via their specific NTR responsiveness.

Synthesis and biological evaluation of 18F-labelled dopamine D3 receptor selective ligands.

The dopamine D3 receptor (D3R) is highly expressed in the limbic regions of the brain and closely related to a variety of neurological disorders including Parkinson's disease, schizophrenia and drug-seeking behavior. In vivo imaging of D3R with radio-labelled tracers and positron emission tomography (PET) has become a powerful technique in related disorders. In this study, we synthesized three novel aromatically 18F-labelled phenylpiperazine-like D3R selective radioactive ligands ([18F]5b, [18F]8b and [18F]11b) and developed a simple, rapid and efficient 18F-labelling method by condition optimization. Radiosynthesis of [18F]5b, [18F]8b and [18F]11b was achieved by 18F-fluorination from nitroarene precursors. Final radiochemical purities of [18F]5b, [18F]8b and [18F]11b solution were > 99% and remained good stability (> 98% for up to 6 h) in PBS and FBS. PET imaging and cellular binding studies revealed that [18F]8b had a higher D3R affinity than [18F]5b and [18F]11b. Autoradiography and biodistribution studies of the brain showed that [18F]8b had medium intensity specific accumulation in the striatum and cortex. Meanwhile, the low skeletal uptake of [18F]8b revealed a good in vivo stability with negligible defluorination. These results indicated that [18F]8b might be a potential 18F-labelled D3R PET imaging agent.

18F-Labelled pyrrolopyrimidines reveal brain leucine-rich repeat kinase 2 expression implicated in Parkinson's disease.

18F-Labelled pyrrolopyrimidines were synthesized and evaluated as positron emission tomography (PET) probes to determine leucine-rich repeat kinase 2 (LRRK2) expression in the brain. With pyrrolopyrimidine derivative PF-06447475 as the lead compound, two in vivo-stable 18F-labelled pyrrolopyrimidines ([18F]1 and [18F]2) were synthesized automatically at radiochemical yields 8-10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/µmol, respectively. The measured Kd of 6.90 nM for 1 and 14.27 nM for 2 demonstrated high affinities for LRRK2. The LRRK2 G2019S mice had higher uptakes (P < 0.01) of [18F]1 in the olfactory bulb, striatum, and hippocampus than WT mice during microPET/CT imaging, consistent with immunohistology results of LRRK2 distribution. [11C]CFT microPET/CT imaging demonstrated a lower expression of dopamine transporter in LRRK2 G2019S mice. Parkinson's disease-like deficits in dopamine transporter synthesis and cognitive declines were noticed along with LRRK2 expression increase in the olfactory bulb, striatum, and hippocampus. Therefore, 18F-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy.

A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride.

Herein we report the mild and rapid fluorodesulfurization of thionoesters using only silver(I) fluoride. This reaction demonstrates excellent functional group tolerance and complements existing strategies for difluoroalkyl ether synthesis, which rely on toxic and often dangerous reagents that demonstrate limited functional group compatibility. We additionally report the translation of this finding to the production of 18 F-labelled difluoroalkyl ethers using fluoride-derived [18 F]AgF. This new process should enable the synthesis of a wide range of difluoroalkyl ethers with applications in medicinal and materials chemistry, and radiotracer production.

Baeyer-Villiger oxidation tuned to chemoselective conversion of non-activated [18 F]fluorobenzaldehydes to [18 F]fluorophenols.

A reaction pathway via oxidation of [18 F]fluorobenzaldehydes offers a very useful tool for the no-carrier-added radiosynthesis of [18 F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer-Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2-trifluoroethanol as reaction solvent in combination with Oxone or m-CPBA as oxidation agent. The studies showed the necessity of H2 SO4 addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2-[18 F]fluorophenol was obtained with a RCY of 97% under optimised conditions of 80°C and 30-minute reaction time. The changed performance of the BVO, which is in agreement with known reaction mechanisms via Criegee intermediates, provided the best results with regard to radiochemical yield (RCY) and chemoselectivity, i.e. formation of [18 F]fluorophenols rather than [18 F]fluorobenzoic acids. Thus, after a long history of the BVO, the new modification now allows an almost specific formation of phenols, even from electron-deficient benzaldehydes. Further, the applicability of the tuned, chemoselective BVO to the n.c.a. level and to more complex compounds was demonstrated for the products n.c.a. 4-[18 F]fluorophenol (RCY 95%; relating to 4-[18 F]fluorobenzaldehyde) and 4-[18 F]fluoro-m-tyramine (RCY 32%; relating to [18 F]fluoride), respectively.