Re-PERFUSE: Phase 1b study of AZD3427, a novel relaxin receptor agonist, on renal perfusion in HFrEF patients.

Aims: Renal impairment frequently coexists with heart failure (HF) and is associated with increased risk of poor clinical outcomes. This highlights the urgent need for therapies targeting both cardiac and renal dysfunction. AZD3427, a long-acting recombinant fusion protein and relaxin analogue that selectively activates the relaxin family peptide receptor 1 (RXFP1), showed trends of increased stroke volume and estimated glomerular filtration rate (eGFR) in HF patients (NCT04630067).

Brain exposure of the mesenchymal-epithelial transition inhibitor savolitinib in nonhuman primates: A positron emission tomography study.

The receptor tyrosine kinase mesenchymal-epithelial transition factor inhibitor savolitinib is currently being evaluated as a treatment in non-small cell lung cancer (NSCLC) in combination with osimertinib. NSCLC patients with epidermal growth factor receptor/anaplastic lymphoma kinase mutations appear to have a high incidence (50%-60%) of brain metastasis; hence, cancer drugs that can efficiently access the brain hold a critical advantage. In this study, savolitinib blood-brain barrier penetration properties were investigated in nonhuman primates using positron emission tomography and intravenous administration of microdoses of [C]savolitinib either as a bolus or a bolus-constant infusion.

Putative mapping of α-subunits in the human brain: A PET study of GABA receptor binding.

The benzodiazepines (BZ) bind to the GABAreceptor (GABAR) at the interface of its α-/γ-subunits and exert pharmacological activity as allosteric modulators. However, the distribution of the six distinct α-subunits (α-α) in the human brain has not been mapped in detail, primarily due to lack of α-subunit selective radioligands. AZD7325 and AZD6280 were two drug candidates with partial α-subunit selectivity, in development for the treatment of anxiety.

Test-retest properties of [C]PXT012253 as a positron emission tomography (PET) radiotracer in healthy human brain: PET imaging of mGlu4.

Background: The metabotropic glutamate receptor 4 (mGlu4) has been proposed as a target for Parkinson’s disease to measure levodopa-induced dyskinesia. [C]PXT012253 is a PET radioligand for mGlu4 (3.4 nM), previously characterized in non-human primates.

Radiolabeling and Preliminary In Vivo Evaluation of the Candidate CCR2 Targeting PET Radioligand [C]AZD2423.

Background: AZD2423 is a high-affinity and selective negative allosteric modulator of the chemokine receptor type 2 (CCR2). This receptor plays important roles in the extravasation and transmigration of monocytes under inflammatory conditions. The aims of the current positron emission tomography (PET) study were as follows: (i) to develop an efficient synthetic method for labeling AZD2423 with carbon-11 (C, t = 20.

High Contrast PET Imaging of Subcortical and Allocortical Amyloid-β in Early Alzheimer's Disease Using [11C]AZD2184.

Background: Deposits of amyloid-β (Aβ) appear early in Alzheimer's disease (AD).

Objective: The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET).

Methods: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184.

[ C]PBB3 binding in Aβ(-) or Aβ(+) corticobasal syndrome.

Corticobasal syndrome (CBS) is associated with 4-repeat tauopathy and/or Alzheimer's disease pathologies. To examine tau and amyloid-β (Aβ) deposits in CBS patients using positron emission tomography (PET). Eight CBS patients and three healthy individuals lacking amyloid pathology underwent PET with [ C]PBB3 for tau imaging, and [ C]AZD2184 for Aβ.

Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [ C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs.

Proof of lung muscarinic receptor occupancy by tiotropium: Translational Positron Emission Tomography studies in non-human primates and humans.

Introduction: Molecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR).

Methods: PET imaging was performed using the muscarinic radioligand [C]VC-002.

Decreased 5-HT binding in mild Alzheimer's disease-A positron emission tomography study.

Decreased 5-HT receptor binding has been associated with Alzheimer's disease (AD) and interpreted as a consequence of neuron loss. The purpose of the present study was to compare [ C]WAY100635 binding to the 5-HT receptor in the hippocampus, entorhinal cortex, amygdala and pericalcarine cortex in mild AD patients and elderly controls. AD patients (n = 7) and elderly control subjects (n = 8) were examined with positron emission tomography (PET) and [ C]WAY100635.

Serotonin 1B receptor density mapping of the human brainstem using positron emission tomography and autoradiography.

The serotonin 1B (5-HT) receptor has lately received considerable interest in relation to psychiatric and neurological diseases, partly due to findings based on quantification using Positron Emission Tomography (PET). Although the brainstem is an important structure in this regard, PET radioligand binding quantification in brainstem areas often shows poor reliability. This study aims to improve PET quantification of 5-HT receptor binding in the brainstem.

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [ C]PBR28 and Machine Learning Analysis.

Background: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA.

Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study.

Background: The protein kinase ataxia telangiectasia mutated (ATM) mediates cellular response to DNA damage induced by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is a novel, highly potent, selective ATM inhibitor designed to cross the blood-brain barrier (BBB) and currently evaluated with radiotherapy in a phase I study in patients with brain malignancies.

Simplified quantification of [F]FE-PE2I PET in Parkinson's disease: Discriminative power, test-retest reliability and longitudinal validity during early peak and late pseudo-equilibrium.

Quantification of dopamine transporter (DAT) availability with [F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium.

Quantification and reliability of [C]VC - 002 binding to muscarinic acetylcholine receptors in the human lung - a test-retest PET study in control subjects.

Background: The radioligand [C]VC-002 was introduced in a small initial study long ago for imaging of muscarinic acetylcholine receptors (mAChRs) in human lungs using positron emission tomography (PET). The objectives of the present study in control subjects were to advance the methodology for quantification of [C]VC-002 binding in lung and to examine the reliability using a test-retest paradigm. This work constituted a self-standing preparatory step in a larger clinical trial aiming at estimating mAChR occupancy in the human lungs following inhalation of mAChR antagonists.

The pro-psychotic metabotropic glutamate receptor compounds fenobam and AZD9272 share binding sites with monoamine oxidase-B inhibitors in humans.

The metabotropic glutamate receptor 5 (mGluR5) ligands fenobam and AZD9272 have been reported to induce psychosis-like adverse events and to bind at unknown, non-GluR5-related, sites. Based on similarities of the regional binding patterns for [C]AZD9272 and the monoamine oxidase-B (MAO-B) radioligand [C]L-deprenyl-D2 in PET studies of the human brain we tested the hypothesis that the unique binding of fenobam and AZD9272 may represent specific binding to the MAO-B. PET data previously acquired for subjects examined using [C]AZD9272 or [C]L-deprenyl-D2 were re-evaluated to assess the correlations between radioligand binding parameters in human brain.

A PET study in healthy subjects of brain exposure of C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancer.

Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of C-labelled osimertinib administered intravenously in subjects with an intact blood-brain barrier.

Pulmonary PET imaging confirms preferential lung target occupancy of an inhaled bronchodilator.

Background: Positron emission tomography (PET) is a non-invasive molecular imaging technique that traces the distribution of radiolabeled molecules in experimental animals and human subjects. We hypothesized that PET could be used to visualize the binding of the bronchodilator drug ipratropium to muscarinic receptors (MR) in the lungs of living non-human primates (NHP). The objectives of this study were two-fold: (i) to develop a methodology for quantitative imaging of muscarinic receptors in NHP lung and (ii) to estimate and compare ipratropium-induced MR occupancy following drug administration via intravenous injection and inhalation, respectively.

Test-retest reliability and convergent validity of (R)-[C]PK11195 outcome measures without arterial input function.

Purpose: The PET radioligand (R)-[C]PK11195 is used to quantify the 18-kDa translocator protein (TSPO), a marker for glial activation. Since there is no brain region devoid of TSPO, an arterial input function (AIF) is ideally required for quantification of binding. However, obtaining an AIF is experimentally demanding, is sometimes uncomfortable for participants, and can introduce additional measurement error during quantification.

PET imaging of [C]PBR28 in Parkinson's disease patients does not indicate increased binding to TSPO despite reduced dopamine transporter binding.

Purpose: To examine the hypothesis that cerebral binding to the 18 kDa translocator protein (TSPO), a marker of microglia activation, is elevated in Parkinson's disease (PD), and to assess the relationship between brain TSPO binding and dopaminergic pathology in PD.

Methods: The radioligand [C]PBR28 was used for quantitative assessment of brain TSPO in 16 control subjects and 16 PD patients. To analyse the relationship between dopaminergic pathology and brain TSPO binding, PET studies of the dopamine transporter (DAT) were undertaken in PD patients using the DAT radioligand [F]FE-PE2I.

Nigrostriatal dopamine transporter availability in early Parkinson's disease.

Background: The imaging of biomarkers for characterization of dopaminergic impairment in Parkinson's disease (PD) is useful for diagnosis, patient stratification, and assessment of treatment outcomes. [ F]FE-PE2I is an improved imaging tool allowing for detailed mapping of the dopamine transporter protein in the nigro-striatal system at the level of cell bodies (substantia nigra), axons, and presynaptic terminals (striatum).

Objectives: The objective of this study was to compare the dopamine transporter protein loss in the presynaptic terminals to that in the cell bodies and axons in early PD patients using [ F](E)-N-(3-iodoprop-2-enyl)-2b-carbofluoroethoxy-3b-(4'-methyl-phenyl) nortropane ([ F]FE-PE2I) and high-resolution PET.

In Vivo Visualization of β-Cells by Targeting of GPR44.

GPR44 expression has recently been described as highly β-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C]AZ12204657, was evaluated for visualization of β-cells in pigs and nonhuman primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess β-cell selectivity of the radiotracer.

Reliability of volumetric and surface-based normalisation and smoothing techniques for PET analysis of the cortex: A test-retest analysis using [C]SCH-23390.

Parametric voxelwise analysis is a commonly used tool in neuroimaging, as it allows for identification of regions of effects in the absence of a strong a-priori regional hypothesis by comparing each voxel of the brain independently. Due to the inherent imprecision of single voxel measurements, spatial smoothing is performed to increase the signal-to-noise ratio of single-voxel estimates. In addition, smoothing compensates for imprecisions in anatomical registration, and allows for the use of cluster-based statistical thresholding.

GABA receptor occupancy by subtype selective GABA modulators: PET studies in humans.

Rationale: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA receptor positive modulators with limited sedative effects.

Objectives: The current study aimed to confirm target engagement at GABA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABA receptor occupancy, and tolerability.