Imaging the translocator protein 18 kDa within cognitive control and declarative memory circuits in virally suppressed people with HIV.

Objectives: Virally suppressed people with HIV (VS-PWH) show heterogeneity in patterns of cognitive dysfunction. To better understand the relationship between the neuroimmune response and cognition, we used PET to image the translocator protein 18 kDa (TSPO). The study examined HIV-serostatus differences in TSPO as well as associations between regional TSPO and select cognitive processes defined using the Research Domain Criteria (RDoC) framework.

A radioligand for in vitro autoradiography of CSF1R in post-mortem CNS tissues.

Background: Reactive microglia and recruited peripheral macrophages contribute to the pathogenesis of Alzheimer's dementia (AD). Monocytes, macrophages and microglia all express the marker colony-stimulating factor 1 receptor (CSF1R). 4-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrrole-2-carboxamide (1) is a high-affinity antagonist for CSF1R.

Hippocampal Availability of the α7 Nicotinic Acetylcholine Receptor in Recent-Onset Psychosis.

Importance: Studies using human postmortem tissue and imaging with positron emission tomography (PET) support a low hippocampal availability of the α7 nicotinic acetylcholine receptor (α7-nAChR) in psychotic conditions, particularly in schizophrenia or schizoaffective disorder (nonaffective psychosis). If validated further, the finding may have implications for clinical diagnosis and treatment.

Objective: To test for lower availability of the α7-nAChR in the hippocampus of individuals with recent-onset psychosis compared with healthy control individuals and its association with lower cognitive performance or higher psychotic symptom burden within recent-onset psychosis.

Evaluation of [F]fluoroestradiol and ChRERα as a gene expression PET reporter system in rhesus monkey brain.

Positron emission tomography (PET) reporter systems are a valuable means of estimating the level of expression of a transgene in vivo. For example, the safety and efficacy of gene therapy approaches for the treatment of neurological and neuropsychiatric disorders could be enhanced via the monitoring of exogenous gene expression levels in the brain. The present study evaluated the ability of a newly developed PET reporter system [F]fluoroestradiol ([F]FES) and the estrogen receptor-based PET reporter ChRERα, to monitor expression levels of a small hairpin RNA (shRNA) designed to suppress choline acetyltransferase (ChAT) expression in rhesus monkey brain.

Investigating the Mechanism of Aluminum Fluoride Chelation.

Aluminum fluoride (AlF) complexes have been used over the past decade to incorporate [F]fluoride into large biomolecules in a highly selective fashion by using relatively facile conditions. However, despite their widespread usage, there are a large number of variations in the reaction conditions, without a definitive discussion provided on the mechanism to understand how these changes would alter the end result. Herein, we report a detailed mechanistic investigation of the reaction, using a mixture of theoretical studies, fluorine-19 and fluorine-18 chemistry, and the consequences it has on the efficient clinical translation of AlF-containing imaging agents.

Imaging Brain Injury in Former National Football League Players.

Importance: Pilot studies that involved early imaging of the 18 kDa translocator protein (TSPO) using positron emission tomography (PET) indicated high levels of TSPO in the brains of active or former National Football League (NFL) players. If validated further in larger studies, those findings may have implications for athletes involved in collision sport.

Objective: To test for higher TSPO that marks brain injury and repair in a relatively large, unique cohort of former NFL players compared with former elite, noncollision sport athletes.

Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits.

Background: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ).

Evaluation of Tetrazine Tracers for Pretargeted Imaging within the Central Nervous System.

The pretargeting approach separates the biological half-life of an antibody from the physical half-life of the radioisotope label, providing a strategy for reducing the radiation burden. A widely explored pretargeting approach makes use of the bioorthogonal click reaction between tetrazines (Tzs) and -cyclooctenes (TCOs), combining the targeting specificity of monoclonal antibodies (mAbs) with the rapid clearance and precise reaction of Tzs and TCOs. Such a strategy can allow for the targeting and imaging (e.

[F]FNDP PET neuroimaging test-retest repeatability and whole-body dosimetry in humans.

Purpose: Soluble epoxide hydrolase (sEH) is an enzyme that shapes immune signaling through its role in maintaining the homeostasis of polyunsaturated fatty acids and their related byproducts. [F]FNDP is a radiotracer developed for use with positron emission tomography (PET) to image sEH, which has been applied to imaging sEH in the brains of healthy individuals. Here, we report the test-retest repeatability of [F]FNDP brain PET binding and [F]FNDP whole-body dosimetry in healthy individuals.

Exploring [C]CPPC as a CSF1R-targeted PET Imaging Marker for Early Parkinson's Disease Severity.

Neuroinflammation through enhanced innate immunity is thought play a role in the pathogenesis of Parkinson's disease (PD). Methods for monitoring neuroinflammation in living patients with PD are currently limited to positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. The colony stimulating factor 1 receptor (CSF1R) plays a crucial role in microglial function, an important cellular contributor to the nervous system's innate immune response.

RO6807936 as a novel positron emission tomography (PET) radiotracer for in vitro and in vivo visualization and quantification of beta-site amyloid precursor protein cleaving enzyme (BACE1) in the rodent and baboon brain.

The beta-site amyloid precursor protein cleaving enzyme (BACE1) is responsible for initiating the generation of beta-amyloid, the major constituent of amyloid plaques in Alzheimer's disease (AD). The purpose of this study was to develop a specific BACE1 radioligand for visualization of the distribution pattern and quantification of the BACE1 protein in the rodent and monkey brain both in vitro by autoradiography and in vivo by positron emission tomography (PET). The BACE1 inhibitor RO6807936 originating from an in-house chemical drug optimization program was selected based on its PET tracer-like physicochemical properties and a favorable pharmacokinetic profile.

Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV.

Objective: Neuroimmune activation is a putative driver of cognitive impairment in people with HIV (PWH), even in the age of modern antiretroviral therapy. Nevertheless, imaging of the microglial marker, the 18 kDa translocator protein (TSPO), with positron emission tomography (PET) in treated PWH has yielded inconclusive findings. One potential reason for the varied TSPO results is a lack of cell-type specificity of the TSPO target.

First-in-human imaging using [C]MDTC: a radiotracer targeting the cannabinoid receptor type 2.

Purpose: We report findings from the first-in-human study of [C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET).

Methods: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [C]MDTC. Five participants also completed a second [C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes.

Multi-timepoint imaging with PSMA-targeted [F]F-Florastamin PET/CT: lesion detection and comparison to conventional imaging.

Objective: The aims of this study were to investigate the utility of [F]F-Florastamin, a novel prostate-specific membrane antigen (PSMA)-targeted PET radiotracer with facile radiochemistry, relative to the conventional imaging for the detection of sties of disease and evaluate the effect of multi-timepoint imaging with [F]F-Florastamin PET on lesion detectability.

Methods: Eight prostate cancer patients with known or suspected recurrence who underwent [F]F-Florastamin PET/CT at 1-h and 2-h imaging time-points were included in this prospective pilot study. [F]F-Florastamin PET images were interpreted visually and quantitatively at both time points and compared with CIM.

Molecular imaging of the association between serotonin degeneration and beta-amyloid deposition in mild cognitive impairment.

Background: Degeneration of the serotonin system has been observed in Alzheimer's disease (AD) and in mild cognitive impairment (MCI). In transgenic amyloid mouse models, serotonin degeneration is detected prior to widespread cortical beta-amyloid (Aβ) deposition, also suggesting that serotonin degeneration may be observed in preclinical AD.

Methods: The differences in the distribution of serotonin degeneration (reflected by the loss of the serotonin transporter, 5-HTT) relative to Aβ deposition was measured with positron emission tomography in a group of individuals with MCI and a group of healthy older adults.

An optimized radiosynthesis of [ F]DK222, a PET radiotracer for imaging PD-L1.

A radiochemical synthesis of [ F]DK222, a peptide binder of programmed death ligand 1 protein, suitable for human PET studies is described, and results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements. In addition, the production is extended to use a commercial synthesizer platform (General Electric FASTlab 2).

Dynamic F-Pretomanid PET imaging in animal models of TB meningitis and human studies.

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality.

Gallium-68-labeled Peptide PET Quantifies Tumor Exposure of PD-L1 Therapeutics.

Purpose: Immune checkpoint therapy (ICT) is currently ineffective in a majority of patients. Tumor drug exposure measurements can provide vital insights into mechanisms involved in the resistance of solid tumors to those therapeutics; however, tools to quantify in situ drug exposure are few. We have investigated the potential of programmed death-ligand 1 (PD-L1) pharmacodynamics, quantified using PET, to inform on the tumor exposure of anti-PD-L1 (aPD-L1) therapeutics.

First-in-human use of C-CPPC with positron emission tomography for imaging the macrophage colony-stimulating factor 1 receptor.

Purpose: Study of the contribution of microglia to onset and course of several neuropsychiatric conditions is challenged by the fact that these resident immune cells often take on different phenotypes and functions outside the living brain. Imaging microglia with radiotracers developed for use with positron emission tomography (PET) allows researchers to study these cells in their native tissue microenvironment. However, many relevant microglial imaging targets such as the 18 kDa translocator protein are also expressed on non-microglial cells, which can complicate the interpretation of PET findings.

An improved radiosynthesis of [ F]FAraG, a PET radiotracer for imaging T-cell activation.

In this concise practitioner protocol, the radiochemical synthesis of 2'-deoxy-2'-[ F]fluoro-9-β-d-arabinofuranosylguanine ([ F]FAraG) suitable for human positron emission tomography (PET) studies is described and the results from validation productions are presented. The high specific activity (sometimes referred to as molar activity) radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements established by the U.S.

6-O-(2-[F]Fluoroethyl)-6-O-Desmethyl-Diprenorphine ([F]FE-DPN) Preferentially Binds to Mu Opioid Receptors In Vivo.

Purpose: 6-O-(2-[F]Fluoroethyl)-6-O-desmethyl-diprenorphine ([F]FE-DPN) is regarded as a non-selective opioid receptor radiotracer.

Procedure: Here, we report the first characterization of [F]FE-DPN synthesized from the novel precursor, 6-O-(2-tosyloxyethoxy)-6-O-desmethyl-3-O-trityl-diprenorphine (TE-TDDPN), using a one-pot, two-step nucleophilic radiosynthesis to image opioid receptors in rats and mice using positron emission tomography.

Results: We also show that [F]FE-DPN and [H]DPN exhibit negligible brain uptake in mu opioid receptor (MOR) knockout mice.

PET/CT imaging of CSF1R in a mouse model of tuberculosis.

Purpose: Macrophages represent an essential means of sequestration and immune evasion for Mycobacterium tuberculosis. Pulmonary tuberculosis (TB) is characterized by dense collections of tissue-specific and recruited macrophages, both of which abundantly express CSF1R on their outer surface. 4-Cyano-N-(5-(1-(dimethylglycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide (JNJ-28312141) is a reported high affinity, CSF1R-selective antagonist.

Regional amyloid correlates of cognitive performance in ageing and mild cognitive impairment.

Beta-amyloid deposition is one of the earliest pathological markers associated with Alzheimer's disease. Mild cognitive impairment in the setting of beta-amyloid deposition is considered to represent a preclinical manifestation of Alzheimer's disease. imaging studies are unique in their potential to advance our understanding of the role of beta-amyloid deposition in cognitive deficits in Alzheimer's disease and in mild cognitive impairment.

11C-Para-aminobenzoic acid PET imaging of S. aureus and MRSA infection in preclinical models and humans.

Tools for noninvasive detection of bacterial pathogens are needed but are not currently available for clinical use. We have previously shown that para-aminobenzoic acid (PABA) rapidly accumulates in a wide range of pathogenic bacteria, motivating the development of related PET radiotracers. In this study, 11C-PABA PET imaging was used to accurately detect and monitor infections due to pyogenic bacteria in multiple clinically relevant animal models.

Dynamic PET-facilitated modeling and high-dose rifampin regimens for orthopedic implant-associated infections.

is a major human pathogen causing serious implant–associated infections. Combination treatment with rifampin (10 to 15 mg/kg per day), which has dose-dependent activity, is recommended to treat orthopedic implant–associated infections. Rifampin, however, has limited bone penetration.