Marc B. Skaddan

Learn More
To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET(More)
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort(More)
The aim of this study is to compare the utility of two positron emission tomography (PET) imaging ligands ((+)-[11C]dihydrotetrabenazine ([11C]DTBZ) and the fluoropropyl analog ([18F]FP-(+)-DTBZ)) that target islet β-cell vesicular monoamine transporter type II to measure pancreatic β-cell mass (BCM). [11C]DTBZ or [18F]FP-(+)-DTBZ was injected, and serial(More)
We have developed PET radioligands for the muscarinic acetylcholine receptor designed to be sensitive to endogenous acetylcholine changes. These radioligands were based on the piperidyl and pyrrolidyl benzilate scaffold and include (R)-N-(2-[18F]fluoroethyl)-3-piperidyl benzilate (1b), (R)-N-(2-[18F]fluoroethyl)-3-pyrrolidyl benzilate (2b), and(More)
A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) =(More)
Although the inhibition of acetylcholinesterase remains the primary treatment of Alzheimer's disease, little is known of the results of increased acetylcholine levels on muscarinic receptor occupancy or function. Using N-(2-[18F]fluoroethyl)-4-piperidyl benzilate ([18F]FEPB), a moderate affinity (Ki = 1.7 nmol/L) nonsubtype-selective muscarinic receptor(More)
The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a noninvasive determination of the estrogen receptor (ER) status of tumor cells. Toward this goal, we have synthesized a number of integrated "3+1" oxorhenium(V) complexes designed to mimic estradiol and a class of nonsteroidal(More)
A mechanistic study of the stoichiometric and catalytic H/D exchange reactions involving cationic iridium complexes is presented. Strong evidence suggests that both stoichiometric and catalytic reactions proceed via a monohydrido-iridium species. Stoichiometric deuterium incorporation reactions introduce multiple deuterium atoms into the organic products(More)
There is currently great interest in developing radiotracers to estimate cortical acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymatic activity in Alzheimer’s disease patients using in vivo imaging. As part of an ongoing effort to define structure-activity relationships (SAR) for cholinesterase substrates, we have recently published in(More)
INTRODUCTION Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development.(More)