Preparation and Preclinical Evaluation of F-Labeled Olutasidenib Derivatives for Non-Invasive Detection of Mutated Isocitrate Dehydrogenase 1 (mIDH1).

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib.

8-Bicycloalkyl-CPFPX derivatives as potent and selective tools for in vivo imaging of the A adenosine receptor.

Imaging of the A adenosine receptor (AR) by positron emission tomography (PET) with 8-cyclopentyl-3-(3-[F]fluoropropyl)-1-propyl-xanthine ([F]CPFPX) has been widely used in preclinical and clinical studies. However, this radioligand suffers from rapid peripheral metabolism and subsequent accumulation of radiometabolites in the vascular compartment. In the present work, we prepared four derivatives of CPFPX by replacement of the cyclopentyl group with norbornane moieties.

Radiosynthesis and In Vitro Evaluation of [C]tozadenant as Adenosine A Receptor Radioligand.

Tozadenant (4-hydroxy--(4-methoxy-7-morpholinobenzo[]thiazol-2-yl)-4-methylpiperidine-1-carboxamide) is a highly selective adenosine A receptor (AR) antagonist and a promising lead structure for the development of AR-selective positron emission tomography (PET) probes. Although several F-labelled tozadenant derivatives showed favorable in vitro properties, recent in vivo PET studies observed poor brain penetration and lower specific binding than anticipated from the in vitro data. While these findings might be attributable to the structural modification associated with F-labelling, they could also reflect inherent properties of the parent compound.

AI-based identification of therapeutic agents targeting GPCRs: introducing ligand type classifiers and systems biology.

Identifying ligands targeting G protein coupled receptors (GPCRs) with novel chemotypes other than the physiological ligands is a challenge for screening campaigns. Here we present an approach that identifies novel chemotype ligands by combining structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model. As a test case, we apply this approach to identify novel antagonists of the human adenosine transmembrane receptor type 2A, an attractive target against Parkinson's disease and cancer.

[F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging.

Selective inhibition of glycine transporter 1 (GlyT1) has emerged as a potential approach to alleviate -methyl-d-aspartate receptor (NMDAR) hypofunction in patients with schizophrenia and cognitive decline. ALX5407 is a potent and selective inhibitor of GlyT1 derived from the metabolic intermediate sarcosine (-methylglycine) that showed antipsychotic potential in a number of animal models. Whereas clinical application of ALX5407 is limited by adverse effects on motor performance and respiratory function, a suitably radiolabeled drug could represent a promising PET tracer for the visualization of GlyT1 in the brain.

Species Differences in Microsomal Metabolism of Xanthine-Derived A Adenosine Receptor Ligands.

Tracer development for positron emission tomography (PET) requires thorough evaluation of pharmacokinetics, metabolism, and dosimetry of candidate radioligands in preclinical animal studies. Since variations in pharmacokinetics and metabolism of a compound occur in different species, careful selection of a suitable model species is mandatory to obtain valid data. This study focuses on species differences in the in vitro metabolism of three xanthine-derived ligands for the A adenosine receptor (AAR), which, in their F-labeled form, can be used to image AAR via PET.

Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A receptor ligands.

With the aim to obtain potent adenosine A receptor (AR) ligands, a series of eighteen derivatives of 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide (SYN-115, Tozadenant) were designed and synthesized. The target compounds were obtained by a chemical building block principle that involved reaction of the appropriate aminobenzothiazole phenyl carbamates with either commercially available or readily synthesized functionalized piperidines. Their affinity and subtype selectivity with regard to human adenosine A-and A receptors were determined using radioligand binding assays.

Delivery of the Radionuclide I Using Cationic Fusogenic Liposomes as Nanocarriers.

Liposomes are highly biocompatible and versatile drug carriers with an increasing number of applications in the field of nuclear medicine and diagnostics. So far, only negatively charged liposomes with intercalated radiometals, e.g.

Development and Evaluation of a Versatile Receptor-Ligand Binding Assay Using Cell Membrane Preparations Embedded in an Agarose Gel Matrix and Evaluation with the Human Adenosine A Receptor.

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Influence of binding affinity and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of two novel xanthine PET radioligands for the A adenosine receptor.

Introduction: The suitability of novel positron emission tomography (PET) radioligands for quantitative in vivo imaging is affected by various physicochemical and pharmacological parameters. In this study, the combined effect of binding affinity, lipophilicity, protein binding and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of three xanthine-derived A adenosine receptor (AAR) radioligands was investigated in rats.

Methods: A comparative evaluation of two novel cyclobutyl-substituted xanthine derivatives, 8-cyclobutyl-3-(3-[F]fluoropropyl)-1-propylxanthine ([F]CBX) and 3-(3-[F]fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine ([F]MCBX), with the reference AAR radioligand 8-cyclopentyl-3-(3-[F]fluoropropyl)-1-propylxanthine ([F]CPFPX) was conducted.

Hypericin and its radio iodinated derivatives - A novel combined approach for the treatment of pediatric alveolar rhabdomyosarcoma cells in vitro.

Background: Alveolar rhabdomyosarcoma (RMA) is a highly malignant soft tissue tumor in children with poor prognosis and failure of established therapies in advanced stages. Therefore, novel treatment options are required. Photodynamic therapy (PDT) has been found useful for the treatment of different tumor entities and might represent such a novel treatment option.

Relevance of In Vitro Metabolism Models to PET Radiotracer Development: Prediction of In Vivo Clearance in Rats from Microsomal Stability Data.

The prediction of in vivo clearance from in vitro metabolism models such as liver microsomes is an established procedure in drug discovery. The potentials and limitations of this approach have been extensively evaluated in the pharmaceutical sector; however, this is not the case for the field of positron emission tomography (PET) radiotracer development. The application of PET radiotracers and classical drugs differs greatly with regard to the amount of substance administered.

Influence of incubation conditions on microsomal metabolism of xanthine-derived A adenosine receptor ligands.

Introduction: In vitro metabolism models such as liver microsomes represent an important tool for the development of novel radioligands. Comparability and physiological relevance of in vitro metabolism data critically depend on the careful evaluation and optimization of assay protocols. We therefore investigated the influence of incubation conditions on the microsomal stability of xanthine-derived A adenosine receptor (AAR) ligands which have been developed for positron emission tomography (PET).

Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A Adenosine Receptor Antagonist 8-Cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX).

The A adenosine receptor (A AR) antagonist [ F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([ F]CPFPX), used in imaging human brain A ARs by positron emission tomography (PET), is stable in the brain, but rapidly undergoes transformation into one major (3-(3-fluoropropyl)-8-(3-oxocyclopenten-1-yl)-1-propylxanthine, M1) and several minor metabolites in blood. This report describes the synthesis of putative metabolites of CPFPX as standards for the identification of those metabolites. Analysis by (radio)HPLC revealed that extracts of human liver microsomes incubated with no-carrier-added (n.

Efficient synthesis of [ F]FPyME: A new approach for the preparation of maleimide-containing prosthetic groups for the conjugation with thiols.

An improved high yielding radiosynthesis of the known thiol-reactive maleimide-containing prosthetic group1-[3-(2-[ F]fluoropyridine-3-yloxy)propyl]pyrrole-2,5-dione ([ F]FPyME) is described. The target compound was obtained by a two-step one-pot procedure starting from a maleimide-containing nitro-precursor that was protected as a Diels-Alder adduct with 2,5-dimethylfurane. Nucleophilic radiofluorination followed by heat induced deprotection through a Retro Diels Alder reaction yielded, after chromatographic isolation, [ F]FPyME with a radiochemical yield of 20% in about 60 min overall synthesis time.

New potent A adenosine receptor radioligands for positron emission tomography.

8-Cyclopentyl-3-(3-[F]fluoropropyl)-1-propylxanthine ([F]CPFPX) is meanwhile an accepted receptor ligand to examine the A adenosine receptor (AAR) in humans by positron emission tomography (PET). A major drawback of this compound is its rather fast metabolic degradation in vivo. Therefore two new xanthine derivatives, namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX.

Collision-induced dissociation studies of caffeine in positive electrospray ionisation mass spectrometry using six deuterated isotopomers and one N1-ethylated homologue.

Rationale: In order to deepen the understanding of electrospray ionisation collision-induced dissociation (ESI-CID) fragmentation reactions of xanthine derivatives for the identification of metabolites using low-resolution liquid chromatography/mass spectrometry (LC/MS) analysis, basic experiments using caffeine (1,3,7-trimethylxanthine) as model compound have been performed.

Methods: Six deuterium isotopomers and one N1-ethylated homologue of caffeine have been synthesized and their ESI fragmentation spectra have been obtained by using LC/MS in combination with either standard or perdeuterated eluent mixtures.

Results: One result of these studies is the finding that the positive charges of the ESI-CID caffeine fragments are caused by the addition of protons.

Synthesis of the main metabolite in human blood of the A1 adenosine receptor ligand [18F]CPFPX.

In human blood, the PET radiotracer [(18)F]CPFPX (1) is metabolized to numerous metabolites, one (M1) being the most prominent in plasma 30 min p.i. Because the mass of injected tracer is < or = 5 nmol, concentrations in plasma are too low to analyze.

Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A2A receptor ligands in rat, mouse and pig brain and first ex vivo results.

The adenosine A(2A) receptor in the basal ganglia is involved in the control of movement and plays a role in movement disorders such as Parkinsonism. Developing ligands to evaluate that receptor by noninvasive methods such as positron emission tomography has a high priority. In vitro radioligand binding guides the selection of ligands for in vivo application.

Metabolism of the A1 adenosine receptor PET ligand [18F]CPFPX by CYP1A2: implications for bolus/infusion PET studies.

The A1 adenosine receptor positron emission tomography (PET) ligand 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX, ) undergoes a fast hepatic metabolism. An optimal design of PET quantitation approaches (e.g.

Metabolism of the A(1)1 adenosine receptor positron emission tomography ligand [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX) in rodents and humans.

Studies of plasma from mice, rats, and human volunteers evaluated methods for the extraction and quantification of the positron emission tomography ligand [(18)F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([(18)F]CPFPX) and identification of its metabolites in plasma by thin-layer chromatography and high-performance liquid chromatography (HPLC). Analysis of human, mouse, and rat plasma extracts by HPLC identified four identical radioactive metabolites in each species. The low mass of radioligand administered to humans (0.

Synthesis and evaluation of 7-amino-2-(2(3)-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines as potential A2A adenosine receptor antagonists for positron emission tomography (PET).

The brain A2A adenosine receptor (A2AAR) participates with the dopamine D2 receptor in the control of movement and also might influence behavior. Because PET is an important tool for studying the roles of receptors in disease, a ligand for imaging the brain A2AAR is desirable. This report describes the synthesis and A2AAR antagonist activities of a panel of phenyl-substituted 7-amino-2-(2-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines, 11aa-af, and their 3-furyl congeners, 11ba-bd.

Derivatives of 4,6-diamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-2H-1-one: potential antagonist ligands for imaging the A2A adenosine receptor by positron emission tomography (PET).

The importance of the brain A2A adenosine receptor (A(2A)AR) in movement disorders urges the development of radiolabeled ligands for imaging those receptors by positron emission tomography (PET). This study evaluated one class of A(2A)AR antagonists, derivatives of 4-amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-2H-1-one, 10a, as agents for imaging brain A(2A)ARs by PET..

Quantification of cerebral A1 adenosine receptors in humans using [18F]CPFPX and PET: an equilibrium approach.

The cerebral A(1) adenosine receptor (A(1)AR) has recently become accessible for in vivo imaging using the selective A(1)AR ligand [(18)F]CPFPX and PET. For broad application in neurosciences, imaging at distribution equilibrium is advantageous to quantify stimulus-dependent changes in receptor availability and to avoid arterial blood sampling. Here we propose a bolus/infusion (B/I) protocol to assess the total distribution volume (DV(t)) of [(18)F]CPFPX under equilibrium conditions.

Quantification of cerebral A1 adenosine receptors in humans using [18F]CPFPX and PET.

Adenosine is an important neuromodulator. Basic cerebral effects of adenosine are exerted by the A1 adenosine receptor (A1AR), which is accessible in vivo by the novel ligand [F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([F]CPFPX) and positron emission tomography (PET). The present study investigates the applicability of kinetic models to describe the cerebral kinetics of [F]CPFPX in order to quantify A1AR density in vivo.