Person: Hooker, Jacob
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Hooker, Jacob
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Publication A Philosophy for CNS Radiotracer Design(American Chemical Society, 2014) Van de Bittner, Genevieve C.; Ricq, Emily; Hooker, JacobConspectus Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.Publication In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs(American Chemical Society, 2014) Wang, Changning; Schroeder, Frederick A.; Wey, Hsiao-Ying; Borra, Ronald; Wagner, Florence F.; Reis, Surya; Kim, Sung Won; Holson, Edward B.; Haggarty, Stephen; Hooker, JacobEpigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [11C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [11C]6 for human epigenetic imaging.Publication Imaging cardiac SCN5A using the novel F-18 radiotracer radiocaine(Nature Publishing Group, 2017) Hooker, Jacob; Strebl, Martin G.; Schroeder, Frederick A.; Wey, Hsiao-Ying; Ambardekar, Amrut V.; McKinsey, Timothy A.; Schoenberger, MatthiasThe key function of the heart, a well-orchestrated series of contractions, is controlled by cardiac action potentials. These action potentials are initiated and propagated by a single isoform of voltage gated sodium channels – SCN5A. However, linking changes in SCN5A expression levels to human disease in vivo has not yet been possible. Radiocaine, an F-18 radiotracer for positron emission tomography (PET), is the first SCN5A imaging agent in the heart. Explants from healthy and failing human hearts were compared using radiocaine autoradiography to determine that the failing heart has ~30% lower SCN5A levels - the first evidence of changes in SCN5A expression in humans as a function of disease. Paving the way for translational imaging, radiocaine proved to exhibit high in vivo specific binding to the myocardium of non-human primates. We envision that SCN5A measurements using PET imaging may serve as a novel diagnostic tool to stratify arrhythmia risk and assess for progression of heart failure in patients with a broad spectrum of cardiovascular diseases.Publication Site-selective 18F fluorination of unactivated C–H bonds mediated by a manganese porphyrin† †Electronic supplementary information (ESI) available: Detailed experimental procedures and spectroscopic data for all new compounds. See DOI: 10.1039/c7sc04545j(Royal Society of Chemistry, 2018) Liu, Wei; Huang, Xiongyi; Placzek, MIchael; Krska, Shane W.; McQuade, Paul; Hooker, Jacob; Groves, John T.The first direct C–H 18F fluorination reaction of unactivated aliphatic sites using no-carrier-added [18F]fluoride is reported. Under the influence of a manganese porphyrin/iodosylbenzene system, a variety of unactivated aliphatic C–H bonds can be selectively converted to C–18F bonds. The mild conditions, broad substrate scope and generally inaccessible regiochemistry make this radio-fluorination a powerful alternate to established nucleophilic substitution for the preparation of 18F labeled radio tracers.Publication Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI(Proceedings of the National Academy of Sciences, 2013) Sander, C. Y.; Hooker, Jacob; Catana, Ciprian; Normandin, Marc; Alpert, Nathaniel; Knudsen, G. M.; Vanduffel, Wim; Rosen, Bruce; Mandeville, JosephThis study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [11C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer.Publication A Receptor-Based Model for Dopamine-Induced fMRI Signal(Elsevier BV, 2013) Mandeville, Joseph; Sander, Christin Y.M.; Jenkins, Bruce; Hooker, Jacob; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel; Rosen, Bruce; Normandin, MarcThis report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations.Publication An Efficient and Practical Radiosynthesis of [11C] Temozolomide(American Chemical Society (ACS), 2012) Moseley, Christian K.; Carlin, Stephen M.; Neelamegam, Ramesh; Hooker, JacobTemozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [11C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [11C]TMZ synthesis and reformulation make it difficult for routine production. A highly reproducible one-pot radiosynthesis of [11C]TMZ with a radiochemical yield of 17 ± 5% and ≥97% radiochemical purity is reported.Publication [11C]PR04.MZ, a Promising DAT Ligand for Low Concentration Imaging: Synthesis, Efficient 11C-O-Methylation and Initial Small Animal PET Studies(Elsevier BV, 2009) Riss, Patrick J.; Hooker, Jacob; Alexoff, David; Kim, Sung-Won; Fowler, Joanna S.; Rösch, FrankPR04.MZ was designed as a highly selective dopamine transporter inhibitor, derived from natural cocaine. Its binding profile indicates that [11C]PR04.MZ may be suited as a PET radioligand for the non-invasive exploration of striatal and extrastriatal DAT populations. As a key feature, its structural design facilitates both, labelling with fluorine-18 at its terminally fluorinated butynyl moiety and carbon-11 at its methyl ester function. The present report concerns the efficient [11C]MeI mediated synthesis of [11C]PR04.MZ from an O-desmethyl precursor trifluoroacetic acid salt with Rb2CO3 in DMF in up to 95 ± 5% labelling yield. A preliminary μPET-experiment demonstrates the reversible, highly specific binding of [11C]PR04.MZ in the brain of a male Sprague–Dawley rat.Publication Metabolic Changes in the Rodent Brain after Acute Administration of Salvinorin A(Springer Nature, 2009) Hooker, Jacob; Patel, Vinal; Kothari, Shiva; Schiffer, Wynne K.Purpose: Salvinorin A (SA) is a potent and highly selective kappa-opioid receptor (KOR) agonist with rapid kinetics and commensurate behavioral effects; however, brain regions associated with these effects have not been determined. Procedures: Freely moving adult male rats were given SA intraperitoneally during uptake and trapping of the brain metabolic radiotracer, 2-deoxy-2-[F-18]fluoro-d-glucose (FDG), followed by image acquisition in a dedicated animal positron emission tomography (PET) system. Age-matched control animals received vehicle treatment. Animal behavior during FDG uptake was recorded digitally and later analyzed for locomotion. Group differences in regional FDG uptake normalized to whole brain were determined using Statistical Parametric Mapping (SPM) and verified by region of interest (ROI) analysis. Results: SA-treated animals demonstrated significant increases in FDG uptake compared to controls in several brain regions associated with the distribution of KOR such as the periaqueductal grey, bed nucleus of the stria terminalis and the cerebellar vermis, as well as in the hypothalamus. Significant bilateral activations were also observed in the auditory, sensory, and frontal cortices. Regional decreases in metabolic demand were observed bilaterally in the dorsolateral striatum and hippocampus. Locomotor activity did not differ between SA and vehicle during FDG uptake. Conclusions: We have provided the first extensive maps of cerebral metabolic activation due to the potent κ-opioid agonist, salvinorin A. A major finding from our small animal PET studies using FDG was that neural circuits affected by SA may not be limited to direct activation or inhibition of kappa-receptor-expressing cells. Instead, salvinorin A may trigger brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output.Publication One-Pot, Direct Incorporation of [11 C]CO 2 into Carbamates(Wiley-Blackwell, 2009) Hooker, Jacob; Reibel, Achim T.; Hill, Sidney M.; Schueller, Michael J.; Fowler, Joanna S.Why beat about the bush? An operationally simple and mild reaction based on the direct fixation of 11CO2 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has been developed for the synthesis of 11C-labeled carbamates at 75 °C within 10 minutes in radiochemical yields above 70 % (see scheme). This strategy should be immediately useful for the construction of new radiotracers for positron emission tomography and other applications.