Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

Purpose: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive.

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [F]SDM-16.

Purpose: To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [C]UCB-A, [C]UCB-J, and [F]SynVesT-1.

Methods: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A.

Further Investigation of Synaptic Vesicle Protein 2A (SV2A) Ligands Designed for Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging: Synthesis and Structure-Activity Relationship of Substituted Pyridinylmethyl-4-(3,5-difluorophenyl)pyrrolidin-2-ones.

A series of synaptic vesicle protein 2A (SV2A) ligands were synthesized to explore the structure-activity relationship and to help further investigate a hydrogen bonding pharmacophore hypothesis. Racemic SynVesT-1 was used as a lead compound to explore the replacement of the 3-methyl group on the pyridinyl moiety with halogens and hydrocarbons. Pyridinyl isomers of racemic SynVesT-1 were also investigated.

Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer C-TASP699.

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V, V, and V). Among these subtypes, the V receptor (VR), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety.

Assessment of test-retest reproducibility of [F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A.

Purpose: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [C]UCB-J.

First-in-Human Evaluation of F-SynVesT-1, a Radioligand for PET Imaging of Synaptic Vesicle Glycoprotein 2A.

The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans. C-UCB-J (()-1-((3-(C-methyl-C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope C.

Body Mass Index and Age Effects on Brain 11β-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study.

Context: Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo.

Synthesis and Preclinical Evaluation of an F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [F]SynVesT-2.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g.

A single-center, open-label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers.

Objective: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer C-UCB-J (EP0074; NCT02602860).

Imaging the Enzyme 11β-Hydroxysteroid Dehydrogenase Type 1 with PET: Evaluation of the Novel Radiotracer C-AS2471907 in Human Brain.

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts cortisone to cortisol and participates in the regulation of glucocorticoid levels in tissues. 11β-HSD1 is expressed in the liver, kidney, adipose tissue, placenta, and brain. 11β-HSD1 is a target for treatment of depression, anxiety, posttraumatic stress disorder, and also against age-related cognitive function and memory loss.

Novel Kappa Opioid Receptor Agonist as Improved PET Radiotracer: Development and in Vivo Evaluation.

The kappa opioid receptor (KOR) is involved in depression, alcoholism, and drug abuse. The current agonist radiotracer C-GR103545 is not ideal for imaging KOR due to its slow tissue kinetics in human. The aim of our project was to develop novel KOR agonist radiotracers with improved imaging properties.

Synthesis and in Vivo Evaluation of a Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates.

Structural disruption and alterations of synapses are associated with many brain disorders including Alzheimer's disease, epilepsy, depression, and schizophrenia. We have previously developed the PET radiotracer C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in nonhuman primates and humans. Here we report the synthesis of a novel radiotracer F-SDM-8 and its in vivo evaluation in rhesus monkeys.

The Search for a Subtype-Selective PET Imaging Agent for the GABA Receptor Complex: Evaluation of the Radiotracer [C]ADO in Nonhuman Primates.

The myriad physiological functions of γ-amino butyric acid (GABA) are mediated by the GABA-benzodiazepine receptor complex comprising of the GABA, GABA, and GABA groups. The various GABA subunits with region-specific distributions in the brain subserve different functional and physiological roles. For example, the sedative and anticonvulsive effects of classical benzodiazepines are attributed to the α subunit, and the α and α subunits mediate the anxiolytic effect.

PET imaging of α nicotinic acetylcholine receptors: a comparative study of [F]ASEM and [F]DBT-10 in nonhuman primates, and further evaluation of [F]ASEM in humans.

Purpose: The α nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α nAChRs PET radioligands, [F]ASEM (3-(1,4-diazabicyclo[3.2.

Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors.

Kappa opioid receptor (KOR) antagonists are potential drug candidates for diseases such as treatment-refractory depression, anxiety, and addictive disorders. PET imaging radiotracers for KOR can be used in occupancy study to facilitate drug development, and to investigate the roles of KOR in health and diseases. We have previously developed two C-labeled antagonist radiotracers with high affinity and selectivity toward KOR.

Synthesis and Evaluation of Gd(III) -Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate-Specific Membrane Antigen.

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast.

Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): efficacy in an animal model for schizophrenia.

Metabotropic glutamate receptor 2 (mGluR2) has been implicated in a variety of CNS disorders, including schizophrenia. Disclosed herein is the development of a new series of allosteric potentiators of mGluR2. Structure-activity relationship studies in conjunction with pharmacokinetic data led to the discovery of indole 5, which is active in an animal model for schizophrenia.

Identification and synthesis of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to the alpha 2 delta-1 subunit of voltage gated calcium channel.

We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha 2 delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC(50)=15 nM) and (S)-22 (IC(50)=30 nM). A potent and selective radioligand, [(3)H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.

N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands of the alpha2delta subunit of voltage gated calcium channels.

A series of N-acridin-9-yl-butane-1,4-diamines were found to be high-affinity ligands of the alpha(2)delta subunit of voltage gated calcium channels. The SAR studies of butane-1,4-diamine side chain resulted in the identification of compound 10 (IC(50)=9 nM), which is more potent than gabapentin (IC(50)=27 nM). Partial saturation of the acridine ring was also pursued and provided a compound with higher binding affinity than 1.