Preparation and Evaluation of Cu-Radiolabled Dual-Ligand Multifunctional Gold Nanoparticles for Tumor Theragnosis.

Gold nanoparticles (AuNPs) are cutting-edge platforms for combined diagnostic and therapeutic approaches due to their exquisite physicochemical and optical properties. Using the AuNPs physically produced by femtosecond pulsed laser ablation of bulk Au in deionized water, with a capping agent-free surface, the conjugation of functional ligands onto the AuNPs can be tunable between 0% and 100% coverage. By taking advantage of this property, AuNPs functionalized by two different types of active targeting ligands with predetermined ratios were fabricated.

Development of Fluorinated NP-59: A Revival of Cholesterol Use Imaging with PET.

Imaging of cholesterol use is possible with the I scintiscanning/SPECT agent NP-59. This agent provided a noninvasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact.

Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging.

Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (HTT), which is the hallmark pathology of neurodegenerative Huntington's disease (HD). Development of a high affinity F radiotracer would enable the study of Huntington's disease pathology using a non-invasive imaging modality, positron emission tomography (PET) imaging. Herein, we report the first synthesis of fluorine-18 imaging agent, 6-(5-((5-(2,2-difluoro-2-(fluoro-F)ethoxy)pyridin-2-yl)methoxy)benzo[]oxazol-2-yl)-2-methylpyridazin-3(2)-one ([F]1), a radioligand for HD and its preclinical evaluation (autoradiography of post-mortem HD brains) and (rodent and non-human primate brain PET).

Fully Automated Radiosynthesis of [C]Guanidines for Cardiac PET Imaging.

Radiolabeled guanidines such as -iodobenzylguanidine (MIBG) find utility in nuclear medicine as both diagnostic imaging agents and radiotherapeutics and, over the years, numerous methods for incorporating radionuclides into guanidines have been developed. In connection with a project developing new positron emission tomography (PET) radiotracers for cardiac sympathetic nerve density, we had cause to prepare [C]3F-PHPOG. However, it quickly became apparent that radiolabeling of guanidine scaffolds with carbon-11 has remained challenging, and historical methods lack compatibility with modern automated radiochemistry synthesis platforms and current Good Manufacturing Practice (cGMP) requirements.

Improved Synthesis of [C]COU and [C]PHXY, Evaluation of Neurotoxicity, and Imaging of MAOs in Rodent Heart.

The radiotracers [C]COU and [C]PHXY are potential PET imaging agents for in vivo studies of monoamine oxidases (MAOs), as previously shown in rodent and primate brain. One-pot, automated methods for the radiosynthesis of [C]PHXY and [C]COU were developed to provide reliable and improved radiochemical yields. Although derived from the structure of the neurotoxin MPTP, COU did not exhibit in vivo neurotoxicity to dopaminergic nerve terminals in the mouse brain as assayed by losses of VMAT2 radioligand binding.

Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE).

The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([F]InRAGER) and extracellular ([F]RAGER) domains of RAGE.

Synthesis and Evaluation of C- and F-Labeled SOAT1 Inhibitors as Macrophage Foam Cell Imaging Agents.

PD-132301, an inhibitor of sterol -acyltransferase 1 (SOAT1; also known as acyl-coenzyme A:cholesterol acyltransferase-1, ACAT1), is under clinical investigation for numerous adrenal disorders. Radiolabeled SOAT1 inhibitors could support drug discovery and help diagnose SOAT1-related disorders, such as atherosclerosis. We synthesized two radiolabeled SOAT1 inhibitors, [C]PD-132301 and fluorine analogue [F].

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys.

Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently.

Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery.

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates.

Synthesis and Initial In Vivo Evaluation of [C]AZ683-A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R).

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (K = 8 nM; IC = 6 nM) and >250-fold selectivity over 95 other kinases. In this paper, we report the radiosynthesis of [C]AZ683 and initial evaluation of its use in CSF1R PET.

Synthesis and pre-clinical evaluation of a potential radiotracer for PET imaging of the dopamine D receptor.

There is considerable interest in using positron emission tomography (PET) imaging to understand the function of dopamine D receptors. Due to high sequence homology with D receptors, development of D-selective PET radiotracers has been challenging. In an effort to overcome this issue, we report the radiosynthesis of a new selective D ligand with carbon-11 ( ), and its initial preclincial evaluation as a potential PET radiotracer for imaging of D receptors.

Automated synthesis of [Ga]oxine, improved preparation of Ga-labeled erythrocytes for blood-pool imaging, and preclinical evaluation in rodents.

Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging. Historically they have been labeled with SPECT radionuclides. A PET blood pool imaging agent is highly desirable as it would improve clinical applications with better image quality and resolution, higher sensitivity, and dynamic scanning capabilities.

Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1.

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule.

Identification of [F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging.

Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first F-labeled optimized lead suitable for in vivo imaging of Trk, [F]TRACK, which is radiosynthesized with ease from a nonactivated aryl precursor concurrently combining largely reduced P-gp liability and improved brain kinetics compared to previous leads while displaying high on-target affinity and human kinome selectivity.

[(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease.

Objective: We wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains.

Methods: To screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aβ rather than synthetic tau aggregates or Aβ fibrils generated in vitro to measure the affinity and selectivity of [(18)F]T807 to tau and Aβ. Brain uptake and biodistribution of [(18)F]T807 in mice were also tested.

A highly selective and specific PET tracer for imaging of tau pathologies.

Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. While there are a number of amyloid-β positron emission tomography (PET) tracers currently in different stages of clinical development and commercialization, there have been very few reports on imaging agents selectively targeting tau aggregates. In search of [18F]-PET tracers that possess great binding affinity and selectivity toward tau tangles, we tested more than 900 compounds utilizing a unique screening process.