Impurity profiling of N,N'-ethylenebis-l-cysteine diethyl ester (Bicisate).

A HPLC-UV-CAD method with a HILIC column for impurity profiling of the 99mTc chelating agent bicisate has been developed and evaluated. Bicisate and its impurities were separated by means of isocratic elution on a zwitterionic stationary phase using a mixture of 7.5mmol/L trifluoroacetic acid and acetonitrile (47.

Pretargeted PET Imaging Using a Bioorthogonal F-Labeled trans-Cyclooctene in an Ovarian Carcinoma Model.

In cancer research, pretargeted positron emission tomography (PET) imaging has emerged as an effective two-step approach that combines the excellent target affinity and selectivity of antibodies with the advantages of using short-lived radionuclides such as fluorine-18. One possible approach is based on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between tetrazines and trans-cyclooctene (TCO) derivatives. Here, we report the first successful use of an F-labeled small TCO compound, [F]1 recently developed in our laboratory, to perform pretargeted immuno-PET imaging.

AlF-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging.

Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The AlF-labeling strategy involves chelation in aqueous medium of aluminum mono[F]fluoride ({AlF}) by a suitable chelator conjugated to a biomolecule.

Synthesis and preclinical evaluation of [C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL).

MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer.

Micro-flow photosynthesis of new dienophiles for inverse-electron-demand Diels-Alder reactions. Potential applications for pretargeted PET imaging.

Pretargeted PET imaging has emerged as an effective two-step approach that combines the superior affinity and selectivity of antibodies with the rapid pharmacokinetics and favorable dosimetry of smaller molecules radiolabeled with short-lived radionuclides. This approach can be based on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between tetrazines and -cyclooctene (TCO) derivatives. We aimed to develop new [F]TCO-dienophiles with high reactivity for IEDDA reactions, and favorable stability and pharmacokinetics.

Preclinical Evaluation of F-JNJ64349311, a Novel PET Tracer for Tau Imaging.

In this study, we have synthesized and evaluated F-JNJ64349311, a tracer with high affinity for aggregated tau (inhibition constant value, 8 nM) and high (≥500×) in vitro selectivity for tau over β-amyloid, in comparison with the benchmark compound F-AV1451 (F-T807) in mice, rats, and a rhesus monkey. In vitro binding characteristics were determined for Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration patient brain tissue slices using autoradiography studies. Ex vivo biodistribution studies were performed in mice.

Striatal phosphodiesterase 10A availability is altered secondary to chronic changes in dopamine neurotransmission.

Background: Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [F]JNJ42259152 PET to measure changes in PDE10A availability, secondary to pharmacological alterations in DA release and to investigate whether these are D- or D-receptor driven.

Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5).

The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5-specific PET tracers.

Synthesis, Biodistribution and Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [C]MA2 and [F]MA3.

The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and evaluation of a carbon-11 ([C]MA2) and a fluorine-18 ([F]MA3) labeled analog of a highly potent -arylamide oxadiazole CB2 agonist (EC = 0.

[18F]JNJ42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic AMP.

Phosphodiesterase 10A (PDE10A) is a key regulator of medium spiny neuron excitability. Therefore, it plays an important role in the regulation of motor, reward, and cognitive processes. Despite the interest in PDE10A as a drug and positron emission tomography (PET) imaging target, little is known about the regulation of PDE10A enzymatic activity.

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2.

Unlabelled: Positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) are a potential therapy for anxiety, schizophrenia, and addiction. Aside from pathophysiologic imaging studies, an mGluR2 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for proof-of-concept studies of PAM compounds. C-JNJ-42491293, a novel high-affinity radioligand (human 50% inhibitory concentration = 9.

Preclinical Evaluation of a P2X7 Receptor-Selective Radiotracer: PET Studies in a Rat Model with Local Overexpression of the Human P2X7 Receptor and in Nonhuman Primates.

Unlabelled: The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclinical evaluation of (11)C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates.

Methods: (11)C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R).

Drug Development in Alzheimer's Disease: The Contribution of PET and SPECT.

Clinical trials aiming to develop disease-altering drugs for Alzheimer's disease (AD), a neurodegenerative disorder with devastating consequences, are failing at an alarming rate. Poorly defined inclusion-and outcome criteria, due to a limited amount of objective biomarkers, is one of the major concerns. Non-invasive molecular imaging techniques, positron emission tomography and single photon emission (computed) tomography (PET and SPE(C)T), allow visualization and quantification of a wide variety of (patho)physiological processes and allow early (differential) diagnosis in many disorders.

Dynamic 68Ga-DOTATOC PET/CT and static image in NET patients. Correlation of parameters during PRRT.

Purpose: To investigate the relationship between the dynamic parameters (Ki) and static image-derived parameters of 68Ga-DOTATOC-PET, to determine which static parameter best reflects underlying somatostatin-receptor-expression (SSR) levels on neuroendocrine tumours (NETs).

Patients, Methods: 20 patients with metastasized NETs underwent a dynamic and static 68Ga-DOTATOC-PET before PRRT and at 7 and 40 weeks after the first administration of 90Y-DOTATOC (in total 4 cycles were planned); 175 lesions were defined and analyzed on the dynamic as well as static scans. Quantitative analysis was performed using the software PMOD.

Comparison of New Tau PET-Tracer Candidates With [18F]T808 and [18F]T807.

Early clinical results of two tau tracers, [(18)F]T808 and [(18)F]T807, have recently been reported. In the present study, the biodistribution, radiometabolite quantification, and competition-binding studies were performed in order to acquire comparative preclinical data as well as to establish the value of T808 and T807 as benchmark compounds for assessment of binding affinities of eight new/other tau tracers. Biodistribution studies in mice showed high brain uptake and fast washout.

New Chelators for Low Temperature Al(18)F-Labeling of Biomolecules.

The Al(18)F labeling method is a relatively new approach that allows radiofluorination of biomolecules such as peptides and proteins in a one-step procedure and in aqueous solution. However, the chelation of the {Al(18)F}(2+) core with the macrocyclic chelators NOTA or NODA requires heating to 100-120 °C. Therefore, we have developed new polydentate ligands for the complexation of {Al(18)F}(2+) with good radiochemical yields at a temperature of 40 °C.

Quantification of TSPO overexpression in a rat model of local neuroinflammation induced by intracerebral injection of LPS by the use of [(18)F]DPA-714 PET.

Purpose: [(18)F]DPA-714 is a radiotracer with high affinity for TSPO. We have characterized the kinetics of [(18)F]DPA-714 in rat brain and evaluated its ability to quantify TSPO expression with PET using a neuroinflammation model induced by unilateral intracerebral injection of lipopolysaccharide (LPS).

Methods: Dynamic small-animal PET scans with [(18)F]DPA-714 were performed in Wistar rats on a FOCUS-220 system for up to 3 h.

PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide.

Objective: The goal of this study was to measure functional and structural aspects of local neuroinflammation induced by intracerebral injection of lipopolysaccharide (LPS) in rats using TSPO microPET imaging with [(18)F]DPA-714, magnetic resonance imaging (MRI), in vitro autoradiography and immunohistochemistry (IHC) in order to characterize a small animal model for screening of new PET tracers targeting neuroinflammation.

Methods: Rats were injected stereotactically with LPS (50 μg) in the right striatum and with saline in the left striatum. [(18)F]DPA-714 microPET, MRI, in vitro autoradiography and IHC studies were performed at different time points after LPS injection for 1 month.

Retention of [(18)F]fluoride on reversed phase HPLC columns.

As [(18)F]fluoride is a starting reagent in the radiosynthesis of most fluorine-18 labeled positron emission tomography (PET) tracers, its chromatographic behavior on reversed phase (RP) HPLC columns is important for the purification performance and accuracy of RP HPLC quality control methods. We have investigated the chromatographic behavior and recovery of [(18)F]fluoride as a function of the type and brand of RP HPLC column, the pH and the composition of the mobile phase. Elution and elution profile of [(18)F]fluoride from six RP-HPLC columns (Waters XBridge C18 3 mm × 100 mm 3.

An overview of translational (radio)pharmaceutical research related to certain oncological and non-oncological applications.

Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult.

Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A.

Introduction: In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands.

Materials & Methods: [(11)C]MP10, [(11)C]JNJ42071965 and four other tracers were developed.

PET radioligands for in vivo visualization of neuroinflammation.

Neuroinflammation is a well-orchestrated, dynamic, multicellular process playing a major role in neurodegenerative disorders. The microglia which make up the innate immune system of the central nervous system are key cellular mediators of neuroinflammatory processes. In normal condition they exert a protective function, providing tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors.

Individualized dosimetry-based activity reduction of ⁹⁰Y-DOTATOC prevents severe and rapid kidney function deterioration from peptide receptor radionuclide therapy.

Purpose: Assessment of kidney function evolution after (90)Y-DOTATOC peptide receptor radionuclide therapy (PRRT) with capped activity administration based on a 37-Gy threshold of biological effective dose (BED) to the kidney.

Methods: In a prospective phase II study, patients with metastasized neuroendocrine tumours were evaluated for therapy using 185 MBq (111)In-pentetreotide with amino acid coinfusion. Planar whole-body images were acquired at four time-points after injection and kidney volumes were measured using CT/MRI.

Sodium cholate, a solubilizing agent for the necrosis avid radioiodinated hypericin in rabbits with acute myocardial infarction.

Objectives: We determined whether sodium cholate (NaCh) could act as a solubilizing agent for the necrosis avid iodine-123-labeled hypericin ((123)I-Hyp) and investigated biodistribution and targetability of this formulation in rabbits with acute myocardial infarction (AMI).

Materials And Methods: Solubility of radioiodinated hypericin/hypericin (Hyp) in NaCh solutions was evaluated by microscopy. Hyp with (123)I-sodium iodide was performed using hydrogen peroxide as oxidant in 0.

Development and biological evaluation of ⁹⁹mTc-sulfonamide derivatives for in vivo visualization of CA IX as surrogate tumor hypoxia markers.

In vivo visualization of tumor hypoxia related markers, such as the endogenous transmembrane protein CA IX may lead to novel therapeutic and diagnostic applications in the management of solid tumors. In this study 4-(2-aminoethyl)benzene sulfonamide (AEBS, K(i) = 33 nM for CA IX) has been conjugated with bis(aminoethanethiol) (BAT) and mercaptoacetyldiglycine (MAG2) tetradendate ligands and the conjugates radiolabelled with (99m)Tc, to obtain anionic and neutral (99m)Tc-labeled sulfonamide derivatives, respectively. The corresponding rhenium analogues were also prepared and showed good inhibitory activities against hCA IX (K(i) = 59-66 nM).