In vivo evaluation of a novel F-labeled PET radioligand for translocator protein 18 kDa (TSPO) in monkey brain.

Purpose: [F]SF51 was previously found to have high binding affinity and selectivity for 18 kDa translocator protein (TSPO) in mouse brain. This study sought to assess the ability of [F]SF51 to quantify TSPO in rhesus monkey brain.

Methods: Positron emission tomography (PET) imaging was performed in monkey brain (n = 3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28.

Candidate 3-benzazepine-1-ol type GluN2B receptor radioligands (C-NR2B-Me enantiomers) have high binding in cerebellum but not to σ1 receptors.

Introduction: We recently reported C-NR2B-SMe ([S-methyl-C](R,S)-7-thiomethoxy-3-(4-(4-methyl-phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol) and its enantiomers as candidate radioligands for imaging the GluN2B subunit within rat N-methyl-D-aspartate receptors. However, these radioligands gave unexpectedly high and displaceable binding in rat cerebellum, possibly due to cross-reactivity with sigma-1 (σ1) receptors. This study investigated C-labeled enantiomers of a close analogue (7-methoxy-3-(4-(p-tolyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol; NR2B-Me) of C-NR2B-SMe as new candidate GluN2B radioligands.

Whole-Body PET Imaging in Humans Shows That C-PS13 Is Selective for Cyclooxygenase-1 and Can Measure the In Vivo Potency of Nonsteroidal Antiinflammatory Drugs.

Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H, which has proinflammatory effects. The recently developed PET radioligand C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of C-PS13 binding to COX-1 in humans and assess the utility of C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs.

Cyclooxygenases as Potential PET Imaging Biomarkers to Explore Neuroinflammation in Dementia.

The most frequently studied target of neuroinflammation using PET is 18-kDa translocator protein, but its limitations have spurred the molecular imaging community to find more promising targets. This article reviews the development of PET radioligands for cyclooxygenase (COX) subtypes 1 and 2, enzymes that catalyze the production of inflammatory prostanoids in the periphery and brain. Although both isozymes produce the same precursor compound, prostaglandin H, they have distinct functions based on their differential cellular localization in the periphery and brain.

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising F-Labeled Ligand.

Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 ( = 109.

[C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

Previous work found that [C]deschloroclozapine ([C]DCZ) is superior to [C]clozapine ([C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hMDi) was injected into the right amygdala of a male rhesus macaque.

Synthesis of [F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey.

Cyclooxygenase-1 (COX-1) and its isozyme COX-2 are key enzymes in the syntheses of prostanoids. Imaging of COX-1 and COX-2 selective radioligands with positron emission tomography (PET) may clarify how these enzymes are involved in inflammatory conditions and assist in the discovery of improved anti-inflammatory drugs. We have previously labeled the selective high-affinity COX-1 ligand, 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1-1,2,4-triazole (PS13), with carbon-11 ( = 20.

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores.