Automated radiosynthesis and preclinical in vivo evaluation of [F]Fluoroethylpuromycin as a potential radiotracer for imaging protein synthesis with PET.

Purpose: From a series of fluorinated analogues of puromycin, we recently identified [F]fluoroethylpuromycin (FEPURO) as a potential candidate for imaging the rate of protein synthesis in vivo. Herein, we describe the automation of the radiosynthesis, and evaluation of [F]FEPURO in vivo.

Procedures: [F]FEPURO was radiosynthesised in an automated module.

Preclinical evaluation of (S)-[F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971.

Purpose: Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [F]GE387, which we have previously shown to have low sensitivity to this polymorphism.

Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models.

Aggregated tau protein is a core pathology present in several neurodegenerative diseases. Therefore, the development and application of positron emission tomography (PET) imaging radiotracers that selectively bind to aggregated tau in fibril form is of importance in furthering the understanding of these disorders. While radiotracers used in human PET studies offer invaluable insight, radiotracers that are also capable of visualizing tau fibrils in animal models are important tools for translational research into these diseases.

Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of αβ Integrin Expression with Gallium-68.

Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (Ga) under mild conditions, and the resulting radiotracers can delineate peptide receptor expression at sites of diseased tissue in vivo. We have synthesized a dendritic bifunctional chelator containing nine 1,6-dimethyl-3-hydroxypyridin-4-one groups (SCN-HP) that can coordinate up to three Ga ions. This derivative has been conjugated to a trimeric peptide (RGD) containing three peptide groups that target the αβ integrin receptor.

[(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity.

Background: [(18)F]BF4 (-), the first (18)F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [(18)F]BF4 (-) with higher SA.

Sigma-1 Agonist Binding in the Aging Rat Brain: a MicroPET Study with [(11)C]SA4503.

Purpose: Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET).

Procedures: Time-dependent uptake of [(11)C]SA4503 was measured in the brain of young (1.

Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses.

Rationale: Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D2 receptor (D2R) antagonists or weak partial agonists and may have pro-mnemonic and neuroprotective effects. The mechanism underlying their stimulatory and neuroprotective actions is unknown but could involve sigma-1R binding.

Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy.

Purpose: Rapid eye movement (REM) sleep deprivation (SD) decreases cerebral sigma-1 receptor expression and causes cognitive deficits. Sigma-1 agonists are cognitive enhancers. Here, we investigate the effect of cutamesine treatment in the REM SD model.

Altered sigma-1 receptor expression in two animal models of cognitive impairment.

Purpose: Sigma-1 receptors are involved in learning and memory processes. We assessed sigma-1 receptor expression and memory function in two animal models of cognitive impairment.

Procedures: Male Wistar-Hannover rats were either lesioned by unilateral injection of N-methyl-D-aspartic acid in the nucleus basalis, or deprived of rapid eye movement sleep for 48 h, using the modified multiple platform method.

Potential applications for sigma receptor ligands in cancer diagnosis and therapy.

Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g.

Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with (11)C-SA4503 and microPET.

Rationale: Sigma-1 receptor agonists are under investigation as potential disease-modifying agents for several CNS disorders. Donepezil, an acetylcholinesterase inhibitor used for the symptomatic treatment of Alzheimer's disease, is also a high-affinity sigma-1 agonist.

Objectives: The objectives of the present study were to investigate if the sigma-1 agonist tracer (11)C-SA4503 and microPET can be used to determine sigma-1 receptor occupancy (RO) of donepezil in the rat brain; to establish RO of donepezil at doses commonly used in rodent behavioural studies; and to determine the effective plasma concentration of donepezil required for 50 % of max-min occupancy (EC50).

[(11)C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain.

The PET tracer [(11)C]5-hydroxytryptophan ([(11)C]5-HTP), which is converted to [(11)C]5-hydroxytryptamine ([(11)C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [(11)C]5-HTP in rat? Male rats were scanned with [(11)C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis.

In vivo responses of human A375M melanoma to a σ ligand: 18F-FDG PET imaging.

Unlabelled: σ-ligands can kill tumor cells. Previously we have shown that a short in vitro incubation of C6 tumor cells with σ-ligands (24 h) results in a dose-dependent increase of cellular (18)F-FDG uptake and that the magnitude of this increase is predictive of subsequent cell death. Here, we aimed to assess whether the σ-ligand rimcazole inhibits growth of A375M melanoma xenografts in nude mice and whether rimcazole treatment changes (18)F-FDG uptake in vivo.

Small-animal PET with a σ-ligand, 11C-SA4503, detects spontaneous pituitary tumors in aged rats.

Unlabelled: Pituitary tumors are often detected only after death or at late stages of the disease when they are macroadenomas with a low surgical cure rate. Spontaneous pituitary tumors occur in rats over 1 y of age. In an ongoing study of changes in σ-1 agonist binding related to aging, several of our rats developed such tumors.

Analysis of 5-HT(2A) receptor binding with [(11)C]MDL 100907 in rats: optimization of kinetic modeling.

Purpose: Preclinical positron emission tomography studies are important to follow disease progression and develop new pharmacological agents. We investigated whether kinetic modeling of 5-HT2A tracer [(11)C]MDL 100907 is possible in rats.

Procedures And Results: Kinetic modeling with either metabolite-corrected plasma curve or with the cerebellum as a reference tissue resulted in a good correlation of nondisplaceable binding potential (BPND) calculated from a two-tissue compartment model (2TCM) or different reference tissue models.

The cholinergic system, sigma-1 receptors and cognition.

This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline).

Synthesis and preclinical evaluation of novel PET probes for P-glycoprotein function and expression.

Unlabelled: P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with (11)C, resulting in potential tracers of P-gp function and expression.

Methods: 6 and 7 were labeled using (11)CH(3)I.