Synthesis and preclinical evaluation of [F]AlF-NODA-MP-C6-CTHRSSVVC as a PET tracer for CD163-positive tumor-infiltrating macrophages.

Positron emission tomography (PET) can provide information about tumor-associated macrophage (TAM) infiltration, as long as a suitable tracer is available. This study aimed to evaluate the radiolabeled peptide [F]AlF-NODA-MP-C6-CTHRSSVVC as a potential PET tracer for imaging of the CD163 receptor, which is expressed on M2-type tumor-associated macrophages. The conjugated peptide NODA-MP-C6-CTHRSSVVC was labeled with aluminum [F]fluoride.

With or without a co-solvent? highly efficient ultrafast phenanthrenequinone-electron rich alkene (PQ-ERA) photoclick reactions.

The light-induced photocycloaddition of 9,10-phenanthrenequinone (PQ) with electron-rich alkenes (ERA), known as the PQ-ERA reaction, is a highly attractive photoclick reaction characterized by its operational simplicity and high biocompatibility. One essential aspect of photoclick reactions is their high rate, however the limited solubility of PQs often requires the use of a co-solvent. Evaluating the effect of different co-solvents on the PQ-ERA reaction and their influence on the reaction rate, we discovered that sulfur-containing compounds, in particular the frequently used solubilizing co-solvent DMSO, quench the triplet state of the PQ.

ImmunoPET provides a novel way to visualize the CD103 tissue-resident memory T cell to predict the response of immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have made significant progress in oncotherapy improving survival of patients. However, the benefits are limited to only a small subgroup of patients who could achieve durable responses. Early prediction of response may enable treatment optimization and patient stratification.

Development of [Zr]Zr-hCD103.Fab01A and [Ga]Ga-hCD103.Fab01A for PET imaging to noninvasively assess cancer reactive T cell infiltration: Fab-based CD103 immunoPET.

Background: CD103 is an integrin specifically expressed on the surface of cancer-reactive T cells. The number of CD103+ T cells significantly increases during successful immunotherapy and might therefore be an attractive biomarker for noninvasive PET imaging of immunotherapy response. Since the long half-life of antibodies preclude repeat imaging of CD103+ T cell dynamics early in therapy, we therefore here explored PET imaging with CD103 Fab fragments radiolabeled with a longer (Zr) and shorter-lived radionuclide (Ga).

Proceedings of international symposium of trends in radiopharmaceuticals 2023 (ISTR-2023).

The International Atomic Energy Agency (IAEA) held the 3rd International Symposium on Trends in Radiopharmaceuticals, (ISTR-2023) at IAEA Headquarters in Vienna, Austria, during the week of 16-21 April 2023. This procedural paper summarizes highlights from symposium presentations, posters, panel discussions and satellite meetings, and provides additional resources that may be useful to researchers working with diagnostic and therapeutic radiopharmaceuticals in the academic, government and industry setting amongst IAEA Member States and beyond. More than 550 participants in person from 88 Member States attended the ISTR-2023.

Postmortem redistribution of amphetamines and benzodiazepines in humans: Important variables that might be influencing the central blood / peripheral blood ratio.

Introduction: The primary objective of postmortem forensic toxicology is to determine if toxicological substances detected in bodily material of victims have contributed to the death of the victim. Interpretation of postmortem drug concentrations is hindered by the fact that time and site dependent variations in postmortem drug concentrations occur, as a result of postmortem redistribution (PMR). An often-used marker for the occurrence of PMR, is the cardiac blood concentration/peripheral blood concentration ratio (C/P ratio) of a drug.

Quantification of P-glycoprotein function at the human blood-brain barrier using [F]MC225 and PET.

Introduction: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression.

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors.

In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow F labeling that could be used for PET imaging.

Effects of proton therapy on regional [F]FDG uptake in non-tumor brain regions of patients treated for head and neck cancer.

Background And Purpose: Previous pre-clinical research using [F]FDG-PET has shown that whole-brain photon-based radiotherapy can affect brain glucose metabolism. This study, aimed to investigate how these findings translate into regional changes in brain [F]FDG uptake in patients with head and neck cancer treated with intensity-modulated proton therapy (IMPT).

Materials And Methods: Twenty-three head and neck cancer patients treated with IMPT and available [F]FDG scans before and at 3 months follow-up were retrospectively evaluated.

Preclinical evaluation of 2-[F]fluorodeoxysorbitol as a tracer for targeted imaging of Enterobacterales infection.

Fluorine-18-fluorodeoxyglucose ([F]FDG) positron emission tomography (F-FDG-PET) is widely used for the detection of inflammatory and infectious diseases. Although this modality has proven to be a useful diagnostic tool, reliable distinction of bacterial infection from sterile inflammation or even from a malignancy remains challenging. Therefore, there is a need for bacteria-specific tracers for PET imaging that facilitate a reliable distinction of bacterial infection from other pathology.

Postmortem redistribution of cocaine and its metabolites, benzoylecgonine and ecgonine methyl ester in humans: Important variables that might be influencing the central blood / peripheral blood ratio.

Introduction: A big challenge in forensic toxicology is the correct interpretation of the results of quantitative analyses in postmortem cases. Postmortem drug concentrations not necessarily reflect the drug concentrations at the time of death, due to postmortem changes in drug concentrations caused by postmortem redistribution (PMR). Cardiac blood is more prone to PMR related concentration changes than peripheral blood.

Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [ F]Canagliflozin in Patients with Type 2 Diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [ F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes.

Development of Zr-anti-CD103 PET imaging for non-invasive assessment of cancer reactive T cell infiltration.

Purpose: CD103, an integrin specifically expressed on the surface of cancer-reactive T cells, is significantly increased during successful immunotherapy across human malignancies. In this study, we describe the generation and zirconium-89 (Zr) radiolabeling of monoclonal antibody (mAb) clones that specifically recognize human CD103 for non-invasive immune positron-emission tomography (PET) imaging of T cell infiltration as potential biomarker for effective anticancer immune responses.

Experimental Design: First, to determine the feasibility of anti-CD103 immuno-PET to visualize CD103-positive cells at physiologically and clinically relevant target densities, we developed an Zr-anti-murine CD103 PET tracer.

A closer look at the synthesis of 2-[F]fluoroethyl tosylate to minimize the formation of volatile side-products.

Background: 2-[F]Fluoroethyltosylate ([F]FEtOTs) is a well-known F-fluoroalkylating agent widely used to synthesize radiotracers for positron emission tomography. The widespread use of [F]FEtOTs is due in part to its low volatility when compared to other halide and sulfonate building blocks. In this work, the radioactive volatile side-products formed during the synthesis of [F]FEtOTs were identified and characterized for the first time, and an optimization of the reaction conditions to minimize their formation was proposed.

Studying Telmisartan Plasma Exposure, Kidney Distribution, Receptor Occupancy, and Response in Patients With Type 2 Diabetes Using [ C]Telmisartan.

The angiotensin receptor blocker telmisartan slows progression of kidney disease in patients with type 2 diabetes (T2D), yet many patients remain at high risk for progressive kidney function loss. The underlying mechanisms for this response variation might be attributed to differences in angiotensin-1 receptor occupancy (RO), resulting from individual variation in plasma drug exposure, tissue drug exposure, and receptor availability. Therefore, we first assessed the relationship between plasma telmisartan exposure and urinary-albumin-to-creatinine-ratio (UACR) in 10 patients with T2D and albuminuria (mean age 66 years, median UACR 297 mg/g) after 4 weeks treatment with 80 mg telmisartan once daily.

Automated Radiosynthesis, Preliminary In Vitro/In Vivo Characterization of OncoFAP-Based Radiopharmaceuticals for Cancer Imaging and Therapy.

FAP-targeted radiopharmaceuticals represent a breakthrough in cancer imaging and a viable option for therapeutic applications. OncoFAP is an ultra-high-affinity ligand of FAP with a dissociation constant of 680 pM. OncoFAP has been recently discovered and clinically validated for PET imaging procedures in patients with solid malignancies.

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D and Histamine H Receptors: A PET Study in Healthy Rats.

: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D/D agonist/H antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET).

Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [F]MC225 and PET.

The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [F]MC225 is a weak P-gp substrate that may show higher sensitivity to detect small changes in P-gp function than previously developed radiotracers. This study explores the sensitivity of [F]MC225 to measure the dose-dependent effect of P-gp inhibitor tariquidar.

Potential PET tracers for imaging of tumor-associated macrophages.

The increasing incidence of cancer over the years is one of the most challenging problems in healthcare. As cancer progresses, the recruitment of several immune cells is triggered. Infiltration of tumor-associated macrophages (TAMs) is correlated with poor patient prognosis.

Expression of CD39 Identifies Activated Intratumoral CD8+ T Cells in Mismatch Repair Deficient Endometrial Cancer.

Identification of human cancer-reactive CD8+ T cells is crucial for the stratification of patients for immunotherapy and determination of immune-therapeutic effects. To date, these T cells have been identified mainly based on cell surface expression of programmed cell death protein 1 (PD-1) or co-expression of CD103 and CD39. A small subset of CD103- CD39+ CD8+ T cells is also present in tumors, but little is known about these T cells.

EANM guideline on quality risk management for radiopharmaceuticals.

This document is intended as a supplement to the EANM "Guidelines on current Good Radiopharmacy Practice (cGRPP)" issued by the Radiopharmacy Committee of the EANM (Gillings et al. in EJNMMI Radiopharm Chem. 6:8, 2021).

A proof-of-concept study on the use of a fluorescein-based F-tracer for pretargeted PET.

Background: Pretargeted immuno-PET tumor imaging has emerged as a valuable diagnostic strategy that combines the high specificity of antibody-antigen interaction with the high signal and image resolution offered by short-lived PET isotopes, while reducing the irradiation dose caused by traditional Zr-labelled antibodies. In this work, we demonstrate proof of concept of a novel 'two-step' immuno-PET pretargeting approach, based on bispecific antibodies (bsAbs) engineered to feature dual high-affinity binding activity for a fluorescein-based F-PET tracer and tumor markers.

Results: A copper(I)-catalysed click reaction-based radiolabeling protocol was developed for the synthesis of fluorescein-derived molecule [F]TPF.