Synthesis and preclinical evaluation of [C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor.

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common.

Development of F-Labeled PET Tracer Candidates for Imaging of the Abelson Non-receptor Tyrosine Kinase in Parkinson's Disease.

Activated Abelson non-receptor tyrosine kinase (c-Abl) plays a harmful role in neurodegenerative conditions such as Parkinson's disease (PD). Inhibition of c-Abl is reported to have a neuroprotective effect and be a promising therapeutic strategy for PD. We have previously identified a series of benzo[]thiazole derivatives as selective c-Abl inhibitors from which one compound showed high therapeutic potential.

Synthesis and Preclinical Evaluation of [-C]brigatinib as a PET Tracer Targeting Both Mutated Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase.

Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4-ALK, has shown a potential to inhibit mutated epidermal growth factor receptor (EGFR). In this study, -desmethyl brigatinib was successfully synthesized as a precursor in five steps. Radiolabeling with [C]methyl iodide produced [-C]brigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/μmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min.

Synthesis and preclinical evaluation of two osimertinib isotopologues labeled with carbon-11 as PET tracers targeting the tyrosine kinase domain of the epidermal growth factor receptor.

Introduction: Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) that is able to inhibit the EGFR treatment resistance mutation T790M and primary EGFR mutations Del19 and L858R. The aim of the study was to evaluate the potential of carbon-11 labeled osimertinib to be used as a tracer for the PET imaging of tumors bearing the T790M mutation.

Methods: Osimertinib was labeled with carbon-11 at two positions, and the effect of the labeling position on the metabolism and biodistribution was studied in female nu/nu mice.

Imaging the TGFβ type I receptor in pulmonary arterial hypertension.

Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([C]LR111 and [F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH.

Validation of simplified uptake measures against dynamic Patlak K for quantification of lesional Zr-Immuno-PET antibody uptake.

Purpose: Positron emission tomography imaging of zirconium-89-labelled monoclonal antibodies (Zr-Immuno-PET) allows for visualisation and quantification of antibody uptake in tumours in vivo. Patlak linearization provides distribution volume (V) and nett influx rate (K) values, representing reversible and irreversible uptake, respectively. Standardised uptake value (SUV) and tumour-to-plasma/tumour-to-blood ratio (TPR/TBR) are often used, but their validity depends on the comparability of plasma kinetics and clearances.

[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant.

Purpose: PET with 16α-[18F]-fluoro-17β-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]-fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER-positive breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant.

Experimental Design: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES).

Synthesis and preclinical evaluation of [C]LR111 and [F]EW-7197 as PET tracers of the activin-receptor like kinase-5.

The transforming growth factor β (TGFβ) pathway plays a complex role in cancer biology, being involved in both tumour suppression as well as promotion. Overactive TGFβ signalling has been linked to multiple diseases, including cancer, pulmonary arterial hypertension, and fibrosis. One of the key meditators within this pathway is the TGFβ type I receptor, also termed activin receptor-like kinase 5 (ALK5).

Relationship between Biodistribution and Tracer Kinetics of C-Erlotinib, F-Afatinib and C-Osimertinib and Image Quality Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis in Advanced Stage Non-Small Cell Lung Cancer Patients.

Background: Patients with non-small cell lung cancer (NSCLC) driven by activating epidermal growth factor receptor (EGFR) mutations are best treated with therapies targeting EGFR, i.e., tyrosine kinase inhibitors (TKI).

Validation and test-retest repeatability performance of parametric methods for [C]UCB-J PET.

[C]UCB-J is a PET radioligand that binds to the presynaptic vesicle glycoprotein 2A. Therefore, [C]UCB-J PET may serve as an in vivo marker of synaptic integrity. The main objective of this study was to evaluate the quantitative accuracy and the 28-day test-retest repeatability (TRT) of various parametric quantitative methods for dynamic [C]UCB-J studies in Alzheimer's disease (AD) patients and healthy controls (HC).

Novel Thienopyrimidine-Based PET Tracers for P2Y Receptor Imaging in the Brain.

The P2Y receptor (P2YR) is uniquely expressed on microglia in the brain, and its expression level directly depends on the microglial activation state. Therefore, P2YR provides a promising imaging marker for distinguishing the pro- and anti-inflammatory microglial phenotypes, both of which play crucial roles in neuroinflammatory diseases. In this study, three P2YR antagonists were selected from the literature, radiolabeled with carbon-11 or fluorine-18, and evaluated in healthy Wistar rats.

Synthesis and evaluation of [F]cinacalcet for the imaging of parathyroid hyperplasia.

Introduction: Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the parathyroid glands is the standard treatment but requires precise pre-operative localization of the glands. However, currently available imaging modalities show limited sensitivity.

Biodistribution of F-FES in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant (G1T48), a Novel Selective ER Degrader.

16α-F-fluoro-17β-estradiol (F-FES) is a PET tracer characterizing the expression of the estrogen receptor (ER). Because therapy can interfere with the kinetics and biodistribution of F-FES, the aim of this study was to describe the biodistribution of F-FES in patients with metastatic ER-positive (ER+) breast cancer undergoing treatment with rintodestrant (G1T48), a novel selective ER degrader. Eight patients underwent F-FES PET/CT imaging at baseline, 4-6 wk during treatment with rintodestrant (interim), and after treatment.

Kinetics and 28-day test-retest repeatability and reproducibility of [C]UCB-J PET brain imaging.

[C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [C]UCB-J PET scans with arterial sampling with an interval of 28 days.

Identifying advanced stage NSCLC patients who benefit from afatinib therapy using F-afatinib PET/CT imaging.

Objectives: Non-small cell lung cancer (NSCLC) tumors harboring common (exon19del, L858R) and uncommon (e.g. G719X, L861Q) activating epidermal growth factor receptor (EGFR) mutations are best treated with EGFR tyrosine kinase inhibitors (TKI) such as the first-generation EGFR TKI erlotinib, second-generation afatinib or third-generation osimertinib.

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

Background: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([F]flortaucipir PET), synaptic density (synaptic vesicle 2A [C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease.

Methods: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [F]flortaucipir PET, dynamic 60-min [C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement.

Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome.

Objectives: The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales.

Materials And Methods: In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks.

Non-invasive Standardised Uptake Value for Verification of the Use of Previously Validated Reference Region for [F]Flortaucipir and [F]Florbetapir Brain PET Studies.

Purpose: The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject.

C-Sorafenib and O-HO PET for Early Evaluation of Sorafenib Therapy.

Sorafenib leads to clinical benefit in a subgroup of patients, whereas all are exposed to potential toxicity. Currently, no predictive biomarkers are available. The purpose of this study was to evaluate whether C-sorafenib and O-HO PET have potential to predict treatment efficacy.

PET imaging of P2XR in the experimental autoimmune encephalomyelitis model of multiple sclerosis using [C]SMW139.

Background: Non-invasive imaging of the activation status of microglia and the ability to identify a pro- or anti-inflammatory environment can provide valuable insights not only into pathogenesis of neuro-inflammatory and neurodegenerative diseases but also the monitoring of the efficacy of immunomodulatory therapies. P2XR is highly expressed on pro-inflammatory microglia and [C]SMW139, a specific P2XR tracer for positron emission tomography imaging, showed good pharmacokinetics, stability, and brain permeability in vivo. Our objective was to evaluate the potential of [C]SMW139 for PET imaging of neuroinflammation in vivo in the experimental autoimmune encephalomyelitis (EAE) model.

Quantification of [F]afatinib using PET/CT in NSCLC patients: a feasibility study.

Introduction: Only a subgroup of non-small cell lung cancer (NSCLC) patients benefit from treatment using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as afatinib. Tumour uptake of [F]afatinib using positron emission tomography (PET) may identify those patients that respond to afatinib therapy. Therefore, the aim of this study was to find the optimal tracer kinetic model for quantification of [F]afatinib uptake in NSCLC tumours.

Effect of the monoaminergic stabiliser (-)-OSU6162 on mental fatigue following stroke or traumatic brain injury.

Objective: The purpose of the present study was to evaluate the efficacy and safety of (-)-OSU6162 in doses up to 30 mg b.i.d.