Min-Liang Pan

University of California, Irvine, Irvine, California, United States

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Publications (30)37.5 Total impact

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    ABSTRACT: Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaques in the brain. The aim of this study was to evaluate the effectiveness of a novel radiotracer, 4-[(11) C]methylamino-4'-N,N-dimethylaminoazobenzene ([(11) C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Methods: Radiosyntheses of [(11) C]TAZA, related [(11) C]Dalene ((11) C-methylamino-4'-dimethylaminostyrylbenzene) and reference [(11) C]PIB were carried out by using [(11) C]methyltriflate prepared from [(11) C]CO2 and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [(3) H]PIB. In vitro autoradiography studies with the three radiotracers were performed on of hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. Results: The 3 radiotracers were produced in high radiochemical yields (>40%) and had specific activities >37 GBq/μmol. TAZA had an affinity, Ki= 0.84 nM and was to be 5 times more potent than PIB. [(11) C]TAZA bound specifically to Aβ plaques present in AD brains with grey matter to white matter ratios >20. [(11) C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [(11) C]TAZA and [(11) C]PIB. [(11) C]TAZA exhibited slow kinetics of uptake in the rat brain and whole body images showed uptake in interscapular brown adipose tissue (IBAT). Binding in brain and IBAT were affected by pre-injection of atomoxetine, a norepinephrine transporter blocker. Conclusion: [(11) C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics were slow and peripheral binding to IBAT needs to be further evaluated. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Synapse
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    Full-text · Dataset · Dec 2015
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    ABSTRACT: 18F-Mefway PET Movie: Normal Human brain showing binding of 18F-Mefway. Summed distribution volume ratio (DVR)whole brain PET image was obtained after intravenous administration of 18F-Mefway (~185 MBq). Binding of 18F-Mefway was the highest in the anterior hippocampus (in white), while the posterior hippocampus had levels comparable to temporal cortical regions.
    Full-text · Dataset · Oct 2015
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    ABSTRACT: We have developed 18F-trans-Mefway (18F-Mefway) for PET imaging studies of serotonin 5-HT1A receptors which are implicated in various brain functions. Translation of imaging the 5-HT1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of 18F-Mefway in normal mice, rats, monkeys and healthy human volunteers. Mefway was found to be very selective with subnanomolar affinity for the serotonin 5-HT1A receptor. Affinities of >55 nM were found for all other human-cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30 M) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P-glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of 18F-Mefway binding. Consistent binding of 18F-Mefway in cortical regions, hippocampus and raphe was observed across all species. 18F-Mefway in the human brain regions correlated with the known postmortem distribution of 5-HT1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in the rodents, while monkeys and humans showed a raphe to cerebellum ratio approximately 3. 18F-Mefway appears to be an effective serotonin 5-HT1A receptor imaging agent in all models including humans. 18F-Mefway therefore may be used to quantify serotonin 5-HT1A receptor distribution in brain regions for the study of various CNS disorders.
    No preview · Article · Oct 2015 · The Journal of Comparative Neurology
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    ABSTRACT: 18F-Mefway PET-MR Movie Normal Human brain showing binding of 18F-Mefway. Summed distribution volume ratio (DVR)whole brain PET image was obtained after intravenous administration of 18F-Mefway (~185 MBq). The PET image was coregistered with the MRI of the same subject. Temporal cortex (in red) had the highest binding while the cerebellum in purple grey had the least binding of 18F-Mefway.
    Full-text · Dataset · Oct 2015
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    ABSTRACT: Identification of dopamine D3 receptors (D3R) in vivo is important to understand several brain functions related to addiction. The goal of this work was to identify D3R binding of the dopamine D2 receptor (D2R)/D3R imaging agent, 18F-fallypride. Brain slices from male Sprague-Dawley rats (n=6) and New Zealand White rabbits (n=6) were incubated with 18F-fallypride and D3R selective agonist (R)-7-OH-DPAT (98-fold D3R selective). Rat slices were also treated with BP 897 (68-fold D3R selective partial agonist) and NGB 2904 (56-fold D3R selective antagonist). In vivo rat studies (n=6) were done on Inveon PET using 18-37 MBq 18F-fallypride and drug-induced displacement by (R)-7-OH-DPAT, BP 897 and NGB 2904. PET/CT imaging of wild type (WT, n=2) and D2R knock-out (KO, n=2) mice were carried out with 18F-fallypride. (R)-7-OH-DPAT displaced binding of 18F-fallypride, both in vitro and in vivo. In vitro, at 10 nM (R)-7-OH-DPAT, 18F-fallypride binding in the rat ventral striatum (VST) and dorsal striatum (DST) and rabbit nucleus accumbens were reduced by ~10-15%. At 10 μM (R)-7-OH-DPAT all regions in rat and rabbit were reduced by ≥85%. In vivo reductions for DST and VST before and after (R)-7-OH-DPAT were: low-dose (0.015mg/kg) DST -22%, VST -29%; high-dose (1.88 mg/kg) DST -58%, VST -77%, suggesting D3R/D2R displacement. BP 897 and NGB 2904 competed with 18F-fallypride in vitro, but unlike BP 897, NGB2904 did not displace 18F-fallypride in vivo. The D2R KO mice lacked 18F-fallypride binding in the DST. In summary, our findings suggest that up to 20% of 18F-fallypride may be bound to D3R sites in vivo.
    Full-text · Article · Sep 2015 · Synapse
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    ABSTRACT: Abstract Body: Objectives: We have developed agonist 18F-nifene for PET imaging studies of nicotinic α4β2 receptors related to tobacco abuse, lung cancer and neurodegeneration [1]. Animal (rodents and monkeys) PET imaging studies demonstrated the high selectivity of 18F-nifene and rapid in vivo kinetics, suitable for a 1-hour scan time which is an advantage over existing technology for imaging this receptor system [2]. First-in-human studies have therefore been pursued. Here we report comparative brain distribution of 18F-nifene in humans versus findings in animal models. Methods: Acute multiple intravenous (IV) dose toxicity (1.6, 20, 40 mg/kg/day on days 1, 3 and 5) of nifene was measured in male and female Sprague-Dawley rats by SRI International. Radiosyntheses of 18F-nifene was carried out with high specific activity 18F-fluoride as reported previously [1,2]. Rodent, monkey and human studies were carried out either on an Inveon MicroPET/CT, MicroPET P4, or Siemen’s ECAT EXACT HR+ scanner. Human 18Fnifene studies were carried out under an FDA approved IND. All studies were carried out after an IV bolus injection of 18F-nfiene (~0.2 for mice, ~0.7 mCi for rats, ~2-3 mCi for monkeys, ~5 mCi for humans) at a specific activity >2Ci/mmol. Isoflurane anesthesia (1.5-3%) was used for rodents and monkeys. Binding of 18F-nifene to α4β2 receptor-rich regions were analyzed using reference regions cerebellum (CB; for rodents and monkeys) and corpus callosum (CC; for humans). Results: Nifene was well tolerated in the rats and histopathology presented no dose-related findings. The maximum tolerated dose (MTD) and no observable adverse effect level (NOAEL) exceed 40 mg/kg/day. Rapid brain uptake of 18F-nifene was observed in all brain regions across all species. Cerebellum (CB) was used as a reference region across all species, except humans. For humans (3 subjects: 1 M, 2 F), corpus callosum (CC) was used as a reference region because of significant 18F-nifene binding in CB. Thalamus (TH) exhibited the highest levels of 18F-nifene with a time to equilibration of ~45mins across all species. Extrathalamic regions such as cortical areas, lateral geniculate, cingulate gyrus and other brain regions were observed in all species and consistent with the known concentration of α4β2 receptors. At equilibrium, 18F-nifene exhibited ratios of: TH/CC~3 (humans), TH/CB~3 (monkeys, rats and mice). Smaller nuclei in the mid-brain (substantia nigra/ventral tegmental area) were more prominent in the human brains. Conclusion: Our first-in-human studies suggest 18F-Nifene to be a safe and effective α4β2 nicotinic receptor imaging agent. Our findings with 18F-nifene suggest homology of the α4β2 receptor-site across rodents, monkeys and humans. 18F-Nifene may be reliably used to quantify α4β2 receptor distribution and pathology in animal models (such as lung cancer [3], learning and memory [4]) for translational human studies. Research Support: NIH R01AG029479 (JM) References: 1. Pichika et al. Nucl. Med. Biol., 33: 295-304, 2006. 2. Hillmer et al. J. Nucl. Med., 53:1471-1480, 2012. 3. Galitovskiy et al. J. Cancer Res & Therapy, 1: 128-137, 2013. 4. Bieszczcad et al. Synapse, 66: 418-434, 2012.
    No preview · Conference Paper · Sep 2015
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    ABSTRACT: Objectives We have developed the agonist 18F-nifene for PET imaging studies of nicotinic α4β2 receptors in various CNS disorders. Upon successful completion of rodent and monkey studies, we report comparative brain distribution of 18F-nifene in humans. Methods Radiosyntheses of 18F-nifene was carried out with high specific activity 18F-fluoride as reported previously. Rodent, monkey and human studies were carried out either on an Inveon MicroPET/CT, MicroPET P4, or Siemen’s HR+ scanner. Human 18F-nifene studies were carried out under an FDA approved IND. All studies were carried out after an IV bolus injection of 18F-nfiene (~0.2 mCi for mice, ~0.7 mCi for rats, ~2-3 mCi for monkeys, ~5 mCi for humans) at a specific activity >2Ci/mmol. Isoflurane anesthesia (1.5-3%) was used for rodents and monkeys. Binding of 18F-nifene to α4β2 receptor-rich regions were analyzed using ASIPro and PMOD. Results Rapid brain uptake of 18F-nifene was observed in all brain regions across all species. Cerebellum (CB) was used as a reference region across all species, except humans. For humans, corpus callosum (CC) was used as a reference region. Thalamus (TH) exhibited the highest levels of 18F-nifene uptake with a time of pseudo equilibrium, indicated by plateau of target/reference curves, of ~45mins across all species. Extrathalamic uptake in regions such as cortical areas, lateral geniculate, cingulate gyrus and other brain regions were observed in all species and consistent with the reported levels of α4β2 receptors. At equilibrium, 18F-nifene exhibited ratios of: TH/CC~3 (humans), TH/CB~3 (monkeys, rats and mice). Conclusions 18F-Nifene appears to be a safe, stable, selective and effective α4β2 nicotinic receptor imaging agent in animal models and humans. Our findings with 18F-nifene suggest homology of the α4β2 receptor-site across species. 18F-Nifene therefore may be reliably used to quantify α4β2 receptor distribution in brain regions for the translational study of various CNS disorders. Research Support NIH R01AG029479
    No preview · Conference Paper · Jun 2015
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    ABSTRACT: Objectives Abnormalities in nicotinic α4β2 acetylcholine receptors (nAChRs) in the brain have been reported in several CNS pathophysiologies. Our efforts now are currently underway to develop and evaluate potential antagonists for PET (18F-Nifrolene), SPECT (123I-Niodene) and PET/SPECT (18F/123I-Niofene). Here we report the general radiosyntheses and biological properties of the three antagonists. Methods 18F labeling was carried out at 95oC (for 18F-Nifrolene, using a tosylate displacement) and 120oC (for 18F-Niofene, using a bromide displacement) for 30 mins. For radioiodination, 5-tributyltin-precursors for 123I-niodene and 123I-niofene were used. Iodination methods included the use of either chloramine-T or H2O2/acetic acid as oxidants. Products were purified by HPLC followed by N-BOC deprotection using 60% CH3CN: 0.1% Et3N, 2.5 ml/min. Rat brain slice autoradiographic studies were carried out with the three radiotracers. PET studies in rats were carried out in Inveon PET. Results Nifrolene, Niodene and Niofene displayed high affinity for the α4β2 nAChRs. 18F radiolabeling provided high radiochemical yields of 18F-Nifrolene, while the yields for 18F-Niofene were lower. Compared to chloramine-T, H2O2/acetic acid provided a higher yield of niofene and cleaner iodination method of the tributyltin precursor (ret time: tributyl tin = 10.5 mins; N-BOC-niofene =13 mins) In vitro autoradiography showed a high thalamus (TH)/cerebellum (CB) ratio (approx. 9) for 18F-Nifrolene and a ratio of 4 for 123I-Niodene. In vivo PET in rats showed rapid uptake in the brain and selective localization in receptor regions with TH/CB >4 for 18F-Nifrolene and >2 for 18F-Niofene. Time to reach pseudoequilibrium was longer for 18F-Nifrolene than 18F-Niofene. Conclusions Nifrolene had greater binding ratios than Niodene and Niofene. These findings suggest that Nifrolene may be a superior antagonist for use in PET, while Niodene and Niofene may allow shorter scan times. Additional studies are needed with Niofene in order to assess its value in PET/SPECT imaging as an antagonist.
    No preview · Conference Paper · Jun 2015
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    ABSTRACT: We report the use of β3-adrenergic receptor mediated activation of rat brain frontal cortex using mirabegron (a selective β3-adrenoceptor agonist), measured by 18F-FDG PET/CT. Another β3-agonis t, CL 316,243, did not have this effect due to impermeability through the blood brain barrier (BBB), while atomoxetine, a norepinephrine transporter blocker, did increase 18F-FDG uptake in the frontal cortex. Mirabegron exhibited a dose-dependent increase in frontal cortex 18F-FDG uptake. These findings suggest a possible use of selective β3-adrenoceptor agonists in reversing regional glucose hypometabolism in the brain. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2015 · Synapse
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    ABSTRACT: Background: A noninvasive method of monitoring the loss of islet cells can provide an earlier and improved diagnosis for therapeutics development of preclinical phases of diabetes. The use of [18F]fallypride, a dopamine D2/D3 receptor radiotracer, has been developed as a surrogate marker to evaluate loss of pancreatic islet cells in a rodent model of type 1 diabetes. Materials and Methods: Healthy Sprague–Dawley rats were administered [18F]fallypride and imaged for 2 h in a positron emission tomography (PET)/computed tomography (CT) scan. Diabetes was then induced in the same rats by administration of streptozotocin, and a PET/CT scan was performed 4 days after establishing diabetes. Pancreata of a separate set of rats were evaluated by insulin immunostaining for loss of islet cells by streptozotocin. Results: Blood glucose levels of 125 mg/dL and 550 mg/dL were established for those rats without and with diabetes, respectively. [18F]Fallypride uptake in the pancreas of both groups of rats was rapid, but the rats with diabetes showed a significantly lower uptake (less than 50%). The specific binding ratio was decreased by 77% in the diabetic rats. Conclusions: [18F]Fallypride can be a useful surrogate marker for monitoring changes in pancreatic islet cells, thus providing a noninvasive method to evaluate efficacy of therapeutics.
    No preview · Article · Sep 2014 · Diabetes Technology & Therapeutics
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    ABSTRACT: Objectives Spinal cord is known to be innervated with dopaminergic cells with catecholaminergic projections arising from the medulla and pons and dopaminergic transmission in the spinal cord is vital for sensory and motor function. Our goal was to evaluate and compare the imaging capability of dopamine D2/D3 receptors in the rat spinal cord using PET ligands 18 F-fallypride and 11C-fallypride. Methods Male Sprague–Dawley rats were used in all in vitro and in vivo studies. Spinal cord and brain sections were used for in vitro autoradiography and ex vivo autoradiography. For in vivo studies animals received a 18 F-fallypride scan or a 11C-fallypride PET scan. The spinal cord and the brain were then harvested, flash-frozen and imaged ex vivo. For in vivo analysis Logan plots with cerebellum as a reference was used to evaluate binding potentials (BP). Tissue ratios were used for ex vivo analysis. Drug effects were evaluated using clozapine, haloperidol and dopamine were evaluated on spinal cord sections in vitro. Results In vitro studies showed 18 F-fallypride binding to superficial dorsal horn (SDH), dorsal horn (DH), ventral horn (VH) and the pars centralis (PC). In the cervical section, the greatest amount of binding appeared to be in the SDH. Ex vivo studies showed approximately 6% of 18 F-fallypride in SDH compared to that observed in the striatum. In vivo analysis of both 18 F-fallypride and 11C-fallypride in the spinal cord were comparable to that in the extrastriatal regions. Haloperidol and clozapine displaced more than 75% of the 18 F-fallypride in spinal cord sections. Conclusions Our studies showed 18 F-fallypride and 11C-fallypride binding in the spinal cord in vitro and in vivo. The binding pattern correlates well with the known distribution of dopamine D2/D3 receptors in the spinal cord. Keywords Spinal cord; Dopamine receptors; PET; 18 F-fallypride; 11C-fallypride
    Full-text · Article · Aug 2014 · Nuclear Medicine and Biology
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    ABSTRACT: Abstract: Elevated levels of histone deacetylases (HDACs) have been indicated in the development of some cancers. HDAC has been imaged using 18F-FAHA and may serve as a marker to study epigenetics. We report evaluation of 18F-FAHA as a probe in the early diagnosis of lung cancer using 18F-FAHA PET/CT studies of A/J mice treated with NNK. 18F-FAHA radiosynthesis was carried out in specific activity of ~2 Ci/μmol. A/J mice were divided into 2 groups: 1. Controls; 2. NNK treatment group with NNK (100 mg/kg, ip, weekly for 4 wks). Mice were injected 100-200 μCi i.v. 18F-FAHA and then scanned in Inveon PET/CT under anesthesia using 2.0% isoflurane. Midbrain, cerebellum and brainstem uptake of 18F-FAHA was displaced by the known HDAC inhibitor, suberanilohydroxamic acid (SAHA) with less than 10% activity remaining. CT revealed presence of lung nodules in 8 to 10-month old NNK mice while control mice were free of tumors. Little uptake of 18F-FAHA was observed in the control mice lungs while significant 18F-FAHA uptake occurred in the lungs of NNK-treated mice with tumor/nontumor >2.0. Ex vivo scans of the excised NNK and control mice lungs confirmed presence of extensive amounts of lung nodules seen by CT and confirmed by 18F-FAHA in the NNK mice with tumor/nontumor >6.0. Our preliminary imaging studies with A/J mice lung cancer model suggest 18F-FAHA PET may allow the study of epigenetic mechanisms involved in NNK-induced tumorigenesis in the lungs.
    Full-text · Article · Jun 2014 · American Journal of Nuclear Medicine and Molecular Imaging
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    ABSTRACT: Background: A noninvasive method of monitoring the loss of islet cells can provide an earlier and improved diagnosis for therapeutics development of preclinical phases of diabetes. The use of [(18)F]fallypride, a dopamine D2/D3 receptor radiotracer, has been developed as a surrogate marker to evaluate loss of pancreatic islet cells in a rodent model of type 1 diabetes. Materials and methods: Healthy Sprague-Dawley rats were administered [(18)F]fallypride and imaged for 2 h in a positron emission tomography (PET)/computed tomography (CT) scan. Diabetes was then induced in the same rats by administration of streptozotocin, and a PET/CT scan was performed 4 days after establishing diabetes. Pancreata of a separate set of rats were evaluated by insulin immunostaining for loss of islet cells by streptozotocin. Results: Blood glucose levels of 125 mg/dL and 550 mg/dL were established for those rats without and with diabetes, respectively. [(18)F]Fallypride uptake in the pancreas of both groups of rats was rapid, but the rats with diabetes showed a significantly lower uptake (less than 50%). The specific binding ratio was decreased by 77% in the diabetic rats. Conclusions: [(18)F]Fallypride can be a useful surrogate marker for monitoring changes in pancreatic islet cells, thus providing a noninvasive method to evaluate efficacy of therapeutics.
    Full-text · Article · May 2014 · Diabetes Technology & Therapeutics
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    ABSTRACT: Background: Brown adipose tissue [BAT] metabolism in vivo is vital for the development of novel strategies in combating obesity and diabetes. Currently, BAT is activated at low temperatures and measured using 2-deoxy-2-18F-fluoro-D-glucose [18F-FDG] positron-emission tomography [PET]. We report the use of b3-adrenergic receptormediated activation of BAT at ambient temperatures using (R, R)-5-[2-[2,3-(3-chlorphenyl)-2-hydroxyethyl-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate, disodium salt [CL316,243] (a selective b3-adrenoceptor agonist) and measured by 18F-FDG PET/computed tomography [CT]. Methods: Control and CL316,243-treated (2 mg/kg) male Sprague-Dawley rats were administered with 18F-FDG for PET/CT studies and were compared to animals at cold temperatures. Receptor-blocking experiments were carried out using propranolol (5 mg/kg). Dose effects of CL316,243 were studied by injecting 0.1 to 1 mg/kg 30 min prior to 18F-FDG administration. Imaging results were confirmed by autoradiography, and histology was done to confirm BAT activation. Results: CL316,243-activated interscapular BAT [IBAT], cervical, periaortic, and intercostal BATs were clearly visualized by PET. 18F-FDG uptake of IBAT was increased 12-fold by CL316,243 vs. 1.1-fold by cold exposure when compared to controls. 18F-FDG uptake of the CL-activated IBAT was reduced by 96.0% using intraperitoneal administration of propranolol. Average 18F-FDG uptake of IBAT increased 3.6-, 3.5-, and 7.6-fold by doses of 0.1, 0.5,and 1 mg/kg CL, respectively. Ex vivo 18F-FDG autoradiography and histology of transverse sections of IBAT confirmed intense uptake in the CL-activated group and activated IBAT visualized by PET. Conclusion: Our study indicated that BAT metabolic activity could be evaluated by 18F-FDG PET using CL316,243 at ambient temperature in the rodent model. This provides a feasible and reliable method to study BAT metabolism. Keywords: BAT, CL316,243, β3-adrenoceptor, 18F-FDG, obesity
    Full-text · Dataset · May 2014
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    ABSTRACT: Background: Brown adipose tissue [BAT] metabolism in vivo is vital for the development of novel strategies in combating obesity and diabetes. Currently, BAT is activated at low temperatures and measured using 2-deoxy-2-18F-fluoro-D-glucose [18F-FDG] positron-emission tomography [PET]. We report the use of b3-adrenergic receptormediated activation of BAT at ambient temperatures using (R, R)-5-[2-[2,3-(3-chlorphenyl)-2-hydroxyethyl-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate, disodium salt [CL316,243] (a selective b3-adrenoceptor agonist) and measured by 18F-FDG PET/computed tomography [CT]. Methods: Control and CL316,243-treated (2 mg/kg) male Sprague-Dawley rats were administered with 18F-FDG for PET/CT studies and were compared to animals at cold temperatures. Receptor-blocking experiments were carried out using propranolol (5 mg/kg). Dose effects of CL316,243 were studied by injecting 0.1 to 1 mg/kg 30 min prior to 18F-FDG administration. Imaging results were confirmed by autoradiography, and histology was done to confirm BAT activation. Results: CL316,243-activated interscapular BAT [IBAT], cervical, periaortic, and intercostal BATs were clearly visualized by PET. 18F-FDG uptake of IBAT was increased 12-fold by CL316,243 vs. 1.1-fold by cold exposure when compared to controls. 18F-FDG uptake of the CL-activated IBAT was reduced by 96.0% using intraperitoneal administration of propranolol. Average 18F-FDG uptake of IBAT increased 3.6-, 3.5-, and 7.6-fold by doses of 0.1, 0.5,and 1 mg/kg CL, respectively. Ex vivo 18F-FDG autoradiography and histology of transverse sections of IBAT confirmed intense uptake in the CL-activated group and activated IBAT visualized by PET. Conclusion: Our study indicated that BAT metabolic activity could be evaluated by 18F-FDG PET using CL316,243 at ambient temperature in the rodent model. This provides a feasible and reliable method to study BAT metabolism. Keywords: BAT, CL316,243, β3-adrenoceptor, 18F-FDG, obesity
    Full-text · Dataset · May 2014
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    ABSTRACT: Pharmacologic approaches to study brown adipocyte activation in vivo with a potential of being translational to humans are desired. The aim of this study was to examine pre- and postsynaptic targeting of adrenergic system for enhancing brown adipose tissue (BAT) metabolism quantifiable by [(18)F]fluoro-2-deoxyglucose ([(18)F]FDG) positron emission tomography (PET)/computed tomography (CT) in mice. A β3-adrenoreceptor selective agonist (CL 316243), an adenylyl cyclase enzyme activator (forskolin) and a potent blocker of presynaptic norepinephrine transporter (atomoxetine), were injected through the tail vein of Swiss Webster mice 30minutes before intravenous (iv) administration of [(18)F]FDG. The mice were placed on the PET/CT bed for 30min PET acquisition followed by 10min CT acquisition for attenuation correction and anatomical delineation of PET images. Activated interscapular (IBAT), cervical, periaortic and intercostal BAT were observed in 3-dimentional analysis of [(18)F]FDG PET images. CL 316243 increased the total [(18)F]FDG standard uptake value (SUV) of IBAT 5-fold greater compared to that in placebo-treated mice. It also increased the [(18)F]FDG SUV of white adipose tissue (2.4-fold), and muscle (2.7-fold), as compared to the control. There was no significant difference in heart, brain, spleen and liver uptakes between groups. Forskolin increased [(18)F]FDG SUV of IBAT 1.9-fold greater than that in placebo-treated mice. It also increased the [(18)F]FDG SUV of white adipose tissue (2.2-fold) and heart (5.4-fold) compared to control. There was no significant difference in muscle, brain, spleen, and liver uptakes between groups. Atomoxetine increased [(18)F]FDG SUV of IBAT 1.7-fold greater than that in placebo-treated mice. There were no significant differences in all other organs compared to placebo-treated mice except liver (1.6 fold increase). A positive correlation between SUV levels of IBAT and CT Hounsfield unit (HU) (R(2)=0.55, p<0.001) and between CT HU levels of IBAT and liver (R(2)=0.69, p<0.006) was observed. The three pharmacologic approaches reported here enhanced BAT metabolism by targeting different sites in adrenergic system as measured by [(18)F]FDG PET/CT.
    Full-text · Article · Jan 2014 · Nuclear Medicine and Biology
  • Jogeshwar Mukherjee · Min-Liang Pan
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    ABSTRACT: Various compounds, compositions, and methods for binding to β-amyloid plaque and norepinephrine transporters are presented. Especially preferred compounds include those with a PET-detectable label.
    No preview · Patent · Nov 2013

  • No preview · Conference Paper · Jun 2013
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    ABSTRACT: Objectives: Alzheimer’s disease (AD) pathology show formation of Aβ-amyloid plaques (Aβ) and neurofibrillary tangles (NFT) which have deleterious effects on neurotransmitter-receptor functions. Our studies report on the interaction between norepinephrine (NE) and Aβ, using radiotracers 11C-PIB, 3H-PIB and 11C-TAZA (4-11C-methyl-4’-N,N-dimethylazodianiline). Methods: Human post-mortem brain sections (AD, n=4, age 77-89, SP Stage C and controls, n=4; age 81-90 SP Stage 0-A) were obtained from UCI ADRC. Hippocampus (HP) and frontal cortex (FC) brain slices (7 μm thick) were washed in TBS and stained with anti-Aβ antibody 4G8. Adjacent slices were incubated with 11C-PIB (5-25 μCi/cc) or 11C-TAZA (25-30 μCi/cc) in 40% ethanol and 3H- PIB (0.03 μCi/cc) in 10% ethanol and 90% PBS at 37 oC for 0.5-1 hr. Competition with NE (10nM- 500μM) was carried out. 10-100 μM PIB was used for nonspecific binding. Regions of interest were drawn and digital light units (DLU)/ mm2 (Optiquant program) were used to quantify the percentage change in binding of the radiotracers. Results: The 4G8 immunostains confirmed the presence of Aβ-amyloid plaques on AD HP and FC sections, while control sections showed minimal plaques. 11C-PIB and 3H-PIB, both showed a consistent >5 ratio between AD versus control brain. The decrease in 11C-PIB binding with the addition of 100μM NE was >50% while the decrease in 3H- PIB binding was >25% in the PBS buffer. Displacement of 11C-PIB and 3H- PIB by NE was dose-dependent, suggesting competitive binding. 11C-TAZA was found to have a decrease in binding of >30%. Because PIB successfully displaced 11C-PIB, 3H- PIB, and 11C-TAZA, it suggests that both tracers may have similar binding sites and thus similar decreasing effect with the addition of NE. Conclusions: Aβ may be a competing binding site for NE and may possibly interrupt NE transmission or have a role in the pathogenesis of AD. 11C/3H-PIB and 11C-TAZA were displaced by NE both in the HP and FC. Further experiments using 3H-NE are underway to examine NE and Aβ interaction. Research Support: NIH/NIA R01AG029479 (JM), R33 AG030524 (JM)
    No preview · Conference Paper · Jun 2013

Publication Stats

113 Citations
37.50 Total Impact Points

Institutions

  • 2011-2016
    • University of California, Irvine
      • • Department of Radiological Sciences
      • • Department of Psychiatry & Human Behavior
      Irvine, California, United States