Metal Protein-Attenuating Compound for PET Neuroimaging: Synthesis and Preclinical Evaluation of [11C]PBT2.

Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc, and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates. Carbon-11 labeled PBT2 was synthesized in 4.8 ± 0.5% (nondecay corrected) radiochemical yield (RCY) at end-of-synthesis, based upon [11C]CH3I (n = 6), with >99% radiochemical purity and 80-90 GBq/µmol molar activity (Am) from the corresponding normethyl precursor. In the nonhuman primate brain, [11C]PBT2 uptake was extensive with peak concentration SUVpeak of 3.2-5.2 within 2.5-4.5 min postinjection in all cortical and subcortical gray matter regions (putamen > caudate > cortex ≫ white matter) followed by rapid washout from normal brain tissues. Furthermore, it is shown that [11C]PBT2 binds specifically in AD human brain tissue in vitro. The results presented here, combined with the clinical data available for PBT2, warrant the evaluation of [11C]PBT2 as an exploratory PET radiotracer in humans.

18 F-Labeling of Sensitive Biomolecules for Positron Emission Tomography.

Positron emission tomography (PET) imaging study of fluorine-18 labeled biomolecules is an emerging and rapidly growing area for preclinical and clinical research. The present review focuses on recent advances in radiochemical methods for incorporating fluorine-18 into biomolecules via "direct" or "indirect" bioconjugation. Recently developed prosthetic groups and pre-targeting strategies, as well as representative examples in 18 F-labeling of biomolecules in PET imaging research studies are highlighted.

Preclinical PET Neuroimaging of [11C]Bexarotene.

Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [(11)C]CO2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [(11)C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [(11)C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system.

Radiocaine: An Imaging Marker of Neuropathic Injury.

Voltage-gated sodium channels (Navs) play a crucial electrical signaling role in neurons. Nav-isoforms present in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While these isoforms, particularly Nav1.7, are implicated in neuropathic pain disorders, changes in the functional state and expression levels of these channels have not been extensively studied in vivo. Radiocaine, a fluorine-18 radiotracer based on the local anesthetic lidocaine, a non-selective Nav blocker, has previously been used for cardiac Nav1.5 imaging using positron-emission tomography (PET). In the present study, we used Radiocaine to visualize changes in neuronal Nav expression after neuropathic injury. In rats that underwent unilateral spinal nerve ligation, PET/MR imaging demonstrated significantly higher uptake of Radiocaine into the injured sciatic nerve, as compared to the uninjured sciatic nerve, for up to 32 days post-surgery. Radiocaine, due to its high translational potential, may serve as a novel diagnostic tool for neuropathic pain conditions using PET imaging.

A domino approach (hydrolysis/dehydrohalogenation/Heck coupling) for the synthesis of styrene sulfonate salts.

A domino approach of hydrolysis/dehydrohalogenation/Heck coupling was used to synthesize styrene sulfonate salts from iodoarenes and chloroethanesulfonyl chloride in good to excellent yields. Methodology was applicable for heterocyclic as well as disubstituted iodoarenes. Some of the key features of this synthetic methodology include the use of phosphine free catalytic system, water as an environmentally friendly solvent, short reaction times, and absence of additives.

Coevolution of Atomic Resolution and Whole-Brain Imaging for Tau Neurofibrillary Tangles.

Neurofibrillary tangle (NFT) imaging methods at the distinct scales of atomic and whole-brain resolutions have coevolved rapidly. Linking these two areas of research provides insight into how and why certain tau radiotracers, using positron emission tomography (PET), bind selectively to certain morphological forms of the NFT fibril. In this Review, a brief history and background for each research area is presented leading to a summary of the current state of knowledge, with a synopsis of PET NFT radiotracers and an outlook for near-term research efforts. The continued integration of information provided at the level of each of these scales of resolution will catalyze the next generation of clinical imaging technique development and enhance our interpretations of them.

Structural Basis for Achieving GSK-3ß 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, [3H]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 [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3ß-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3ß/GSK-3α) GSK-3ß inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/ß-catenin signaling activation, was observed in cells.

Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3ß Ligands for Positron Emission Tomography Imaging.

Dysregulation of glycogen synthase kinase-3ß (GSK-3ß) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3ß radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3ß and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3ß inhibitors. Radiosynthesis of a potential GSK-3ß tracer [18F]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [18F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted.

A domino approach of Heck coupling for the synthesis of ß-trifluoromethylstyrenes.

A domino approach of Heck coupling was used to synthesize ß-trifluoromethylstyrene derivatives from iodoarenes and 1-iodo-3,3,3-trifluoropropane in moderate to good yields. This method avoids the use of low-boiling, gaseous reagents such as 3,3,3-trifluoropropene, and additives and phosphines in the catalytic system.