Victor W Pike

National Institute of Mental Health (NIMH), 베서스다, Maryland, United States

Are you Victor W Pike?

Claim your profile

Publications (295)963.94 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Imaging ATP-binding cassette (ABC) transporter activity in vivo with positron emission tomography requires both a substrate and a transporter inhibitor. However, for ABCG2, there is no inhibitor proven to be specific to that transporter alone at the blood-brain barrier. Ko143, a non-toxic analog of fungal toxin fumitremorgin C, is a potent inhibitor of ABCG2, although its specificity in mouse and human systems is unclear. This study examined the selectivity of Ko143 using human embryonic kidney cell lines transfected with ABCG2, ABCB1, or ABCC1 in several in vitro assays. The stability of Ko143 in rat plasma was measured using high performance liquid chromatography. Our results show that in addition to being a potent inhibitor of ABCG2, at higher concentrations (≥ 1 μM) Ko143 also has an effect on the transport activity of both ABCB1 and ABCC1. Furthermore, Ko143 was found to be unstable in rat plasma. These findings indicate that Ko143 lacks specificity for ABCG2 and should be taken into consideration when using Ko143 for both in vitro and in vivo experiments. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 07/2015; DOI:10.1124/jpet.115.225482 · 3.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. The [11C]PBR28 distribution volume (VT) corrected for free fraction (fP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. The [11C]PBR28 VT to fp ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [11C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [11C]PBR28 was increased significantly in thalamus. Relative [11C]PBR28 and [11C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([11C]PBR28: 2%-6%; [11C]DPA-713: 4%-9%). Asymmetry of [11C]DPA-713 was greater than that of [11C]PBR28 (F = 29.4; P = .001). Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.
    06/2015; DOI:10.1001/jamaneurol.2015.0941
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non-human primates using the novel CB1R antagonist radioligand [(11)C]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CB1R with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around ∼20-30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of 'neutral' vs. 'classical' CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [(11)C]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 03/2015; DOI:10.1016/j.neuropharm.2015.03.002 · 4.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is associated with increase in brain of the 18 kDa translocator protein (TSPO), which is over-expressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because a reference region devoid of TSPO does not exist in brain. We sought to determine whether a simple ratio method could substitute for absolute quantitation of binding with (11)C-PBR28, a second generation radioligand for TSPO. (11)C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment (MCI), and 25 AD patients. Group differences in (11)C-PBR28 binding were compared using two methods. First, the "gold standard" method of calculating total distribution volume (VT), using the two-tissue compartmental model with the arterial input function, corrected for plasma free fraction of radiotracer (fP). Second, a ratio of brain uptake in target regions to that in cerebellum-i.e., standardized uptake value ratio (SUVR). Using absolute quantitation, we confirmed that TSPO binding (VT/fP): 1) was greater in AD patients than in healthy controls in expected temporo-parietal regions, and 2) was not significantly different among the three groups in cerebellum. Using the cerebellum as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in one additional region, suggesting SUVR may have greater sensitivity. Coefficients of variation of SUVR measurements were about two-thirds lower than those of absolute quantification, and the resulting statistical significance was much higher for SUVR when comparing AD and healthy controls (e.g. P < 0.0005 for SUVR vs. P = 0.023 for VT/fP in combined middle and inferior temporal cortex). To measure TSPO density in AD and control subjects, a simple ratio method SUVR can substitute for, and may even be more sensitive than, absolute quantitation. The SUVR method is expected to improve subject tolerability by allowing shorter scan time and not requiring arterial catheterization. In addition, this ratio method allows smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 03/2015; 56(5). DOI:10.2967/jnumed.114.146027 · 5.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier (BBB) and its resultant 'spare capacity' requires substantial blockade to increase the uptake of avid substrates. This has blunted the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined two P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and two routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-desmethyl-loperamide (dLop), while avoiding side effects associated with high doses of tariquidar. Forty-two (11)C-dLop positron emission tomography (PET) scans were obtained from 37 healthy volunteers. PET was performed with (11)C-dLop under five conditions: 1) injected under baseline conditions without P-gp inhibition; 2) injected one hour after IV tariquidar infusion; 3) injected during IV tariquidar infusion; 4) injected after oral tariquidar; and 5) injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in brain from 10 to 30 minutes. Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in brain uptake of radioligand approximately five-fold greater than baseline. Brain uptake was similar with 2 and 4 mg/kg IV tariquidar; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of IV tariquidar, resulted in greater P-gp inhibition at the human BBB than delayed administration, and allowed use of a lower, more tolerable dose of tariquidar. Based on prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 12/2014; DOI:10.2967/jnumed.114.146894 · 5.56 Impact Factor
  • Gregory R Naumiec, Lisheng Cai, Victor W Pike
    [Show abstract] [Hide abstract]
    ABSTRACT: An expansive set of N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-d-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positron-emitter, carbon-11 (t1/2=20.4min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [(3)H]TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([(123)I]CNS1261). The 3'-dimethylamino (19; Ki 36.7nM), 3'-trifluoromethyl (20; Ki 18.3nM) and 3'-methylthio (2; Ki 39.8nM) derivatives of N-1-naphthyl-N'-(phenyl)-N'-methylguanidine were identified as especially attractive leads for PET radioligand development. Copyright © 2014. Published by Elsevier Ltd.
    Bioorganic & Medicinal Chemistry Letters 11/2014; 25(2). DOI:10.1016/j.bmcl.2014.11.066 · 2.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The imaging of translocator 18kDa protein (TSPO) in living human brain with radioligands by positron emission tomography (PET) has become an important means for the study of neuroinflammatory conditions occurring in several neuropsychiatric disorders. The widely used prototypical PET radioligand, [(11)C](R)-PK 11195 ([(11)C](R)-1; [N-methyl-(11C)](R)-N-sec-butyl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide), gives low PET signal and is difficult to quantify, whereas later generation radioligands have binding sensitivity to a human single nucleotide polymorphism (SNP) rs6971, which imposes limitations on their utility for comparative quantitative PET studies of normal and diseased subjects. Recently, azaisosteres of 1 have been developed with improved drug-like properties, including enhanced TSPO affinity accompanied by moderated lipophilicity. Here we selected three of these new ligands (7-9) for labeling with carbon-11 and for evaluation in monkey as candidate PET radioligands for imaging brain TSPO. Each radioligand was readily prepared by (11)C-methylation of an N-desmethyl precursor and was found to give a high proportion of TSPO-specific binding in monkey brain. One of these radioligands [(11)C]7, the direct 4-azaisostere of 1, presents many radioligand properties that are superior to those reported for [(11)C]1, including higher affinity, lower lipophilicity and stable quantifiable PET signal. Importantly, 7 was also found to show very low sensitivity to the human SNP rs6971 in vitro. Therefore, [(11)C]7 now warrants evaluation in human subjects with PET to assess its utility for imaging TSPO in human brain, irrespective of subject genotype.
    ACS Chemical Neuroscience 08/2014; 5(10). DOI:10.1021/cn500138n · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The serotonin subtype-4 (5-HT4) receptor, which is known to be involved physiologically in learning and memory, and pathologically in Alzheimer’s disease, anxiety and other neuropsychiatric disorders - has few radioligands readily available for imaging in vivo. We have previously reported two novel 5-HT4 receptor radioligands, namely [methoxy-11C](1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [11C]RX-1) and the [18F]3-fluoromethoxy analog ([18F]RX-2), and in this study we evaluated them by PET in rhesus monkey. Brain scans were performed at baseline, receptor preblock or displacement conditions using SB 207710, a 5-HT4 receptor antagonist, on the same day for [11C]RX-1 and on different days for [18F]RX-2. Specific-to-nondisplaceable ratio (BPND) was measured with the simplified reference tissue model from all baseline scans. To determine specific binding, total distribution volume (VT) was also measured in some monkeys by radiometabolite-corrected arterial input function after ex vivo inhibition of esterases from baseline and blocked scans. Both radioligands showed moderate to high peak brain uptake of radioactivity (2–6 SUV). Regional BPND values were in the rank order of known 5-HT4 receptor distribution with a trend for higher BPND values from [18F]RX-2. One-tissue compartmental model provided good fits with well identified VT values for both radioligands. In the highest 5-HT4 receptor density region, striatum, 50–60% of total binding was specific. The VT in receptor-poor cerebellum reached stable values by about 60 min for both radioligands indicating little influence of radiometabolites on brain signal. In conclusion, both [11C]RX-1 and [18F]RX-2 showed positive attributes for PET imaging of brain 5-HT4 receptors, validating the radioligand design strategy. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Synapse 08/2014; 68(12). DOI:10.1002/syn.21773 · 2.43 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction A radioligand for measuring the density of corticotrophin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)pyrazin-2(1H)-one scaffold. Methods CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [125I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [3H]BMS-728300. Results The three ligands selected for development showed high binding affinity (IC50 values, 0.3–8 nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8–4.4). [3H]BMS-728300 and the two 18 F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50 − 120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [18 F]BMS-721313, [18 F]BMS-732098 and [11C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.
    Nuclear Medicine and Biology 07/2014; 41(6). DOI:10.1016/j.nucmedbio.2014.03.005 · 2.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Translocator protein (18kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such studies. There is an unmet need for genotype-insensitive, high-affinity and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development. To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side-chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11. From this effort oxygen-tethered N-methyl-aryloxypropanamides emerged as new high-affinity TSPO ligands with attenuated lipophilicity, including one example with attractive properties for PET radioligand development, namely N-methyl-N-phenyl-2-{[2-(pyridin-2-yl)quinolin-4-yl]oxy}propanamide (22a; rat Ki = 0.10 nM; human TSPO genotypes Ki = 1.4 nM; clogD = 4.18).
    Journal of Medicinal Chemistry 06/2014; 57(14). DOI:10.1021/jm5007947 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Image-derived input function (IDIF) obtained by manually drawing carotid arteries (manual-IDIF) can be reliably used in [(11)C](R)-rolipram positron emission tomography (PET) scans. However, manual-IDIF is time consuming and subject to inter- and intra-operator variability. To overcome this limitation, we developed a fully automated technique for deriving IDIF with a supervised clustering algorithm (SVCA). To validate this technique, 25 healthy controls and 26 patients with moderate to severe major depressive disorder (MDD) underwent T1-weighted brain magnetic resonance imaging (MRI) and a 90-minute [(11)C](R)-rolipram PET scan. For each subject, metabolite-corrected input function was measured from the radial artery. SVCA templates were obtained from 10 additional healthy subjects who underwent the same MRI and PET procedures. Cluster-IDIF was obtained as follows: 1) template mask images were created for carotid and surrounding tissue; 2) parametric image of weights for blood were created using SVCA; 3) mask images to the individual PET image were inversely normalized; 4) carotid and surrounding tissue time activity curves (TACs) were obtained from weighted and unweighted averages of each voxel activity in each mask, respectively; 5) partial volume effects and radiometabolites were corrected using individual arterial data at four points. Logan-distribution volume (V T/f P) values obtained by cluster-IDIF were similar to reference results obtained using arterial data, as well as those obtained using manual-IDIF; 39 of 51 subjects had a V T/f P error of <5%, and only one had error >10%. With automatic voxel selection, cluster-IDIF curves were less noisy than manual-IDIF and free of operator-related variability. Cluster-IDIF showed widespread decrease of about 20% [(11)C](R)-rolipram binding in the MDD group. Taken together, the results suggest that cluster-IDIF is a good alternative to full arterial input function for estimating Logan-V T/f P in [(11)C](R)-rolipram PET clinical scans. This technique enables fully automated extraction of IDIF and can be applied to other radiotracers with similar kinetics.
    PLoS ONE 02/2014; 9(2):e89101. DOI:10.1371/journal.pone.0089101 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth-an animal model of human childhood stress-were also studied. METHOD At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration. RESULTS Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures. CONCLUSIONS Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.
    American Journal of Psychiatry 01/2014; 171(3). DOI:10.1176/appi.ajp.2013.13020183 · 13.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for α1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. The functional assay was performed using (35)S-GTPγS (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with α1 adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains. CUMI-101 did not stimulate (35)S-GTPγS binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated (35)S-GTPγS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant α1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (>45%) and lowest in the neocortex and cerebellum (<10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased (11)C-CUMI-101 brain uptake to that of self-block. CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent α1 adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans.
    Journal of Nuclear Medicine 01/2014; 55(1):141-6. DOI:10.2967/jnumed.113.125831 · 5.56 Impact Factor
  • Source
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Here we aimed to explore the feasibility of enhancing the fluorination of organosilanes by appending potassium-chelating groups to the substrates. For this purpose, eight organosilanes were prepared in which a linear or cyclic leaving group, with putative potassium-chelating ability, was attached covalently to a congested silicon atom via an ether linkage to serve as a potential nucleophilic assisting leaving group (NALG). Organosilicon-NALGs with expected strong potassium-chelating capability enhanced reactions with potassium fluoride in acetonitrile to produce organfluorosilanes without any need to separately add phase transfer reagent. Similar rate enhancements were also observed with cyclotron-produced [18F]fluoride ion (t1/2 = 109.7 min, β+ = 97%) in the presence of potassium carbonate in MeCN-0.5% H2O. This study found that metal-chelating NALG units can accelerate fluorination and radiofluorination reactions at sterically crowded silicon atoms.
    Journal of Fluorine Chemistry 11/2013; 158. DOI:10.1016/j.jfluchem.2013.12.005 · 1.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: [(11)C]NOP-1A is a novel high-affinity PET ligand for imaging nociceptin/orphanin FQ peptide (NOP) receptors. Here, we report reproducibility and reliability measures of binding parameter estimates for [(11)C]NOP-1A binding in brain of healthy humans After intravenous injection of [(11)C]NOP-1A PET scans were conducted twice on eleven healthy volunteers on the same (10/11 subjects) or different (1/11 subjects) days. Subjects underwent serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (VT a measure of receptor density) was determined by compartmental (one- and two- tissue) modeling in large regions and by simpler regression methods (graphical Logan and bilinear MA1) in both large regions and voxel data. Retest variability and intraclass correlation coefficient (ICC) of VT were determined as measures of reproducibility and reliability respectively Regional [(11)C]NOP-1A uptake in brain was high, with a peak radioactivity concentration of 4 - 7 SUV (standardized uptake value) and a rank order of putamen > cingulate cortex > cerebellum. Brain time-activity curves fitted well in 10 of 11 subjects by unconstrained two-tissue compartmental model. The retest variability of VT was moderately good across brain regions except cerebellum, and was similar across different modeling methods, averaging 12% for large regions and 14% for voxel-based methods. The retest reliability of VT was also moderately good in most brain regions, except thalamus and cerebellum, and was similar across different modeling methods averaging 0.46 for large regions and 0.48 for voxels having gray matter probability > 20%. The lowest retest variability and highest retest reliability of VT was achieved by compartmental modeling for large regions, and by the parametric Logan method for voxel-based methods. Moderately good reproducibility and reliability measures of VT for [(11)C]NOP-1A make it a useful PET ligand for comparing NOP receptor binding between different subject groups or under different conditions in the same subject.
    NeuroImage 11/2013; 87. DOI:10.1016/j.neuroimage.2013.10.068 · 6.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4 Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [(18)F]11 in useful radiochemical yield and in high specific activity from [(18)F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [(18)F]11 gave high brain radioactivity uptake reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated a very high proportion of the radioactivity in monkey brain to be bound specifically and reversibly to mGluR1. [(18)F]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects.
    Journal of Medicinal Chemistry 10/2013; 56(22). DOI:10.1021/jm4012017 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We recently developed a novel cannabinoid subtype-1 (CB1) receptor radioligand (11)C-SD5024 for brain imaging. This study aimed to evaluate (11)C-SD5024 both in vitro and in vivo and compare it with the other CB1 receptor ligands previously used in humans, i.e., (11)C-MePPEP, (11)C-OMAR, (18)F-MK-9470, and (18)F-FMPEP-d2. In vitro experiments were performed to measure dissociation constant (Ki) in human brain and to measure the lipophilicity of five CB1 receptor ligands listed above. In vivo specific binding in monkeys was measured by comparing total distribution volume (VT) at baseline and after full receptor blockade. The kinetics of (11)C-SD5024 in humans were evaluated in seven healthy subjects with compartmental modeling. SD5024 showed Ki=0.47 nM, which was at an intermediate level among the five CB1 receptor ligands. Lipophilicity (LogD7.4) was 3.79, which is appropriate for brain imaging. Monkey scans showed high proportion of specific binding: ~80% of VT. In humans, (11)C-SD5024 showed peak brain uptake of 1.5-3 standardized uptake value, which was slightly higher than those of (11)C-OMAR and (18)F-MK-9470. One-compartment model showed good fitting, consistent with the vast majority of brain uptake being specific binding found in the monkey. Regional VT values were consistent with known distribution of CB1 receptors. VT calculated from 80 and 120min of scan data were strongly correlated (R(2)=0.97), indicating that 80min provided adequate information for quantitation and that the influence of radiometabolites was low. Intersubject variability for VT of (11)C-SD5024 was 22%, which was low among the five radioligands and indicated precise measurement. In conclusion, (11)C-SD5024 has appropriate affinity and lipophilicity, high specific binding, moderate brain uptake, and provides good precision to measure the binding. The results suggest that (11)C-SD5024 is slightly better than or equivalent to (11)C-OMAR and that both are suitable for clinical studies, especially those that involve two scans in one day.
    NeuroImage 09/2013; 84. DOI:10.1016/j.neuroimage.2013.09.043 · 6.36 Impact Factor

Publication Stats

6k Citations
963.94 Total Impact Points


  • 2002–2015
    • National Institute of Mental Health (NIMH)
      • • Molecular Imaging Branch
      • • Division of Intramural Research Programs
      베서스다, Maryland, United States
  • 2014
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 2012
    • Northern Inyo Hospital
      BIH, California, United States
  • 2008–2011
    • East China University of Science and Technology
      Shanghai, Shanghai Shi, China
  • 2009
    • University of Texas Southwestern Medical Center
      • Department of Psychiatry
      Dallas, Texas, United States
  • 2007
    • Yonsei University
      Sŏul, Seoul, South Korea
  • 2006–2007
    • National Institutes of Health
      Maryland, United States
  • 2005
    • University of Illinois at Chicago
      • College of Pharmacy
      Chicago, IL, United States
  • 2001
    • Keele University
      Newcastle-under-Lyme, England, United Kingdom
  • 1994–2001
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom
  • 1997
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 1984–1987
    • Medical Research Council (UK)
      Londinium, England, United Kingdom