Exploration of Fluorinated Pyrazolidine-3,5-Diones for Positron Emission Tomography Imaging of the P2Y Receptor in the Central Nervous System.

The purinergic receptor P2Y (P2YR) has emerged as a promising biomarker for selectively imaging the anti-inflammatory phenotype of microglia. Developing positron emission tomography (PET) tracers for this target is an active area of research, as imaging of specific microglial phenotypes can provide valuable insights into their dynamics in neuroinflammation. A key challenge is identifying high affinity P2YR ligands with optimal properties for targeting this receptor in the central nervous system (CNS).

Imaging Proinflammatory Microglia in Parkinson Disease Using [C]SMW139 PET: A Multicenter Study.

Several translocator protein (TSPO) PET studies have shown increased glial cell density in Parkinson disease (PD); however, TSPO tracers are not able to differentiate between proinflammatory and antiinflammatory processes, information that is crucial for the development and evaluation of therapies. We used [C]SMW139 PET to target the P2X7 receptor, which is expressed on proinflammatory microglia, to investigate proinflammatory signals in PD. Patients with PD ( = 15) and healthy controls (HCs) ( = 15) were included in this multicenter study.

SUVs Versus Dynamic Pharmacokinetic [F]Fluoro-Polyethylene Glycol-Folate Uptake Parameters in Joints of Rheumatoid Arthritis Patients at Baseline and at 4 Weeks of Antitumor Necrosis Factor Therapy.

Quantitative assessment of rheumatoid arthritis (RA) activity using [F]fluoro-polyethylene glycol (PEG)-folate PET/CT scans may prove a useful noninvasive therapeutic response assessment tool to evaluate antitumor necrosis factor therapy in RA patients. This study aims to assess [F]fluoro-PEG-folate kinetics through a metabolite-corrected plasma input model and to investigate comparisons with simplified quantitative PET outcome measures. Dynamic [F]fluoro-PEG-folate PET/CT scans were obtained for 6 patients for a total of 11 scans, 6 before and 5 after treatment.

A Radiolabeled Photoswitchable G Protein-Coupled Receptor Antagonist Enlightens Ligand Binding Kinetics Associated with Photoswitching.

Photopharmacology offers powerful opportunities to control protein signaling using photoresponsive ligands. Despite the vast potential of photoswitchable ligands for spatiotemporal target protein control, research on ligand-protein binding kinetics of these ligands remains limited. Herein, we describe the discovery of the first radiolabeled photoswitchable ligand, [H]VUF26063 ([H]), to assess light-dependent ligand-protein binding kinetics in real time.

Whole-Body [F]DPA-714 Kinetic Assessment Using PET/CT Scanner with Long Axial Field of View.

Multisystemic inflammation might be a key pathophysiologic mechanism in post-coronavirus disease 2019 (post-COVID) syndrome. diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a] pyrimidin-3-yl)acetamide ([F]DPA-714), which binds with high affinity the translocator protein (TSPO) receptor, is used as a marker of inflammation. Therefore, quantifying [F]DPA-714 uptake throughout the body could assess extracerebral inflammation in post-COVID syndrome.

Characterization of [H]AZ12464237 as a high affinity, non-nucleotide antagonist radioligand for the P2Y receptor.

The purinergic receptor P2Y (P2YR) is a well-recognized target for anti-thrombotic agents. This receptor is also expressed in microglia, the main immune cells of the brain, where it modulates microglial activation states and inflammatory responses. To investigate P2YR-mediated actions in the central nervous system (CNS), developing novel brain-penetrant ligands and further in vitro studies on brain tissues are essential.

The Diagnostic Accuracy of F-FDG PET and F-FES PET for Staging Grade 1-2 Estrogen Receptor-Positive Breast Cancer.

Background According to current guidelines, staging of patients with locally advanced breast cancer and local-regional recurrent breast cancer is preferably performed with PET using 2-fluorine 18-fluoro-2-deoxy-d-glucose (F-FDG). However, F-FDG PET might underperform in low-grade estrogen receptor (ER)-positive breast cancer. Alternatively, 16α-F-fluoro-17β-estradiol (F-FES) has emerged as a powerful tracer for in vivo visualization of ER-positive lesions.

Development and evaluation of [C]DPA-813 and [F]DPA-814: novel TSPO PET tracers insensitive to human single nucleotide polymorphism rs6971.

Purpose: The translocator protein 18 kDa (TSPO) is a widely used marker for imaging neuroinflammation via Positron Emission Tomography (PET). However, the vast majority of reported TSPO PET tracers display low binding affinity to a common isoform of human TSPO (rs6971; A147T), making them unsuitable for universal use in the general population. In this study, we have developed and preclinically validated two novel tracers designed to image TSPO in patients of all genotypes.

Triflyl [F]Fluoride as a Solution for Base-Sensitive Late-Stage Nucleophilic Aromatic F-Fluorination Reactions.

Fluorine-18 is the predominant radionuclide used to label Positron Emission Tomography (PET) tracers. One outstanding challenge in nucleophilic aromatic radiofluorination reactions is the sensitivity of precursors and catalysts for basic reaction conditions, which are necessary for the work-up of [F]fluoride, resulting in limited reproducibility. Triflyl [F]fluoride is a new [F]fluoride source that allows freedom in choice of type and amounts of base and cryptand.

[F]Trifluoroiodomethane - Enabling Photoredox-mediated Radical [F]Trifluoromethylation for Positron Emission Tomography.

The development of new tracers for positron emission tomography (PET) is highly dependent on the available synthetic tools for their radiosynthesis. Herein, we present the radiosynthesis and application of [F]trifluoroiodomethane - the first reagent for broad scope radical [F]trifluoromethylation chemistry in high molar activity. CF FI can be prepared from [F]fluoroform with 67±5 % AY and >99 % RCP.

Investigation of the Impact of the H310A FcRn Region Mutation on Zr-Immuno-PET Brain Imaging with a BBB-Shuttle Anti‑Amyloid Beta Antibody.

Purpose: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB).

Circulating T cell status and molecular imaging may predict clinical benefit of neoadjuvant PD-1 blockade in oral cancer.

Background: Addition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome.

Methods: In this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response.

Navigating the landscape of PD-1/PD-L1 imaging tracers: from challenges to opportunities.

Immunotherapy targeted to immune checkpoint inhibitors, such as the program cell death receptor (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, it is now well-known that PD-1/PD-L1 immunotherapy response is inconsistent among patients. The current challenge is to customize treatment regimens per patient, which could be possible if the PD-1/PD-L1 expression and dynamic landscape are known.

Advancing Parkinson's Disease Diagnostics: The Potential of Arylpyrazolethiazole Derivatives for Imaging α-Synuclein Aggregates.

The development of positron emission tomography (PET) tracers capable of detecting α-synuclein (α-syn) aggregates in vivo would represent a breakthrough for advancing the understanding and enabling the early diagnosis of Parkinson's disease and related disorders. It also holds the potential to assess the efficacy of therapeutic interventions. However, this remains challenging due to different structures of α-syn aggregates, the need for selectivity over other structurally similar amyloid proteins, like amyloid-β (Aβ), which frequently coexist with α-syn pathology, and the low abundance of the target in the brain that requires the development of a high-affinity ligand.

Synthesis of F-labelled aryl trifluoromethyl ketones with improved molar activity.

A method for the radiosynthesis of F-labelled aryl trifluoromethyl ketones starting from widely available Weinreb amides using [F]fluoroform is presented. The method uses potassium hexamethyldisilazane as base and delivers products in high molar activity (up to 24 GBq μmol) and excellent radiochemical conversions. The applicability for PET tracer synthesis is demonstrated by the radiosynthesis of ten (hetero)aryl trifluoromethylketones, bearing electron-withdrawing and -donating substituents including a derivative of bioactive probenecid.

Challenges in Pharmacokinetic Modelling of [F]fluoro-PEG-folate PET/CT Imaging in Epithelial Ovarian Cancer Patients.

Purpose: To describe the pharmacokinetic properties of the [F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC).

Procedures: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v.

Synthesis of F-labeled Aryl Trifluoromethyl Sulfones, -Sulfoxides, and -Sulfides for Positron Emission Tomography.

Positron emission tomography (PET) is becoming increasingly important in nuclear medicine and drug discovery. To date, the development of many potential PET tracers is hampered by the lack of suitable synthetic pathways for their preparation. This is particularly true for the highly desired radiolabeling of compounds bearing [F]CF-groups.

Validation of image-derived input function using a long axial field of view PET/CT scanner for two different tracers.

Background: Accurate image-derived input function (IDIF) from highly sensitive large axial field of view (LAFOV) PET/CT scanners could avoid the need of invasive blood sampling for kinetic modelling. The aim is to validate the use of IDIF for two kinds of tracers, 3 different IDIF locations and 9 different reconstruction settings.

Methods: Eight [F]FDG and 10 [F]DPA-714 scans were acquired respectively during 70 and 60 min on the Vision Quadra PET/CT system.