Search

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-[11C]methylamino-4′- N, N-dimethylaminoazobenzene ([11C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Methods: Radiosyntheses of [11C]TAZA, related [11C]Dalene (11C-methylamino-4′-dimethylaminostyrylbenzene), and reference [11C]PIB were carried out using [11C]methyltriflate prepared from [11C]CO2 and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [3H]PIB. In vitro autoradiography studies with the three radiotracers were performed on hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. Results: The three 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 five times more potent than PIB. [11C]TAZA bound specifically to Aβ plaques present in AD brains with gray matter to white matter ratios >20. [11C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [11C]TAZA and [11C]PIB. [11C]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 preinjection of atomoxetine, a norepinephrine transporter blocker. Conclusion: [11C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics was slow and peripheral binding to IBAT needs to be further evaluated. Synapse, 2016. © 2016 Wiley Periodicals, Inc. Synapse 70:163-176, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) plays a significant role in metabolism. In this study, we report the use of atomoxetine (a clinically applicable norepinephrine reuptake inhibitor) for 18F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous 18F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before 18F-FDG administration. To confirm the β-adrenergic effects, propranolol (β-adrenergic inhibitor) 5 mg/kg was given intraperitoneally 30 min prior to atomoxetine administration. The effect of atomoxetine on BAT metabolism was assessed in fasted and non-fasted rats and on BAT temperature and blood glucose in fasted rats. In 18F-FDG PET/CT images, interscapular BAT (IBAT) and other areas of BAT were clearly visualized. When rats were fasted, atomoxetine (0.1 mg/kg) increased the 18F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average 18F-FDG uptake of IBAT significantly. Autoradiography of IBAT and white adipose tissue confirmed the data obtained by PET. When rats were not fasted, atomoxetine-induced increase of 18F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of β3-adrenreceptors in non-fasted rats with CL-316, 243 occurred within 30 min. Atomoxetine-induced IBAT activation was associated with higher IBAT temperature and lower blood glucose. This was mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norepinephrine concentration in the synapse. Increased synaptic norepinephrine activates β3-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by 18F-FDG PET/CT. Synapse, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this study, we compared two different D receptor ligands, [F]fallypride and [F]desmethoxyfallypride ([F]DMFP) with respect to the duration of the scan, visualization of extrastriatal receptors, and binding potentials (BP) in the rat brain. In addition, we studied the feasibility of using these tracers following a period of awake tracer uptake, during which the animal may perform a behavioral task. Male Sprague-Dawley rats were imaged with [F]fallypride and with [F]DMFP in four different studies using microPET. All scans were performed under isoflurane anesthesia. The first (test) and second (retest) study were 150-min baseline scans. No retest scans were performed with [F]DMFP. A third study was a 60-min awake uptake of radiotracer followed by a 90-min scan. A fourth study was a 150-min competition scan with haloperidol (0.2 mg/kg) administered via tail vein at 90-min post-[F]fallypride injection and 60-min post-[F]DMFP. For the test-retest studies, BP was measured using both Logan noninvasive (LNI) method and the interval ratios (ITR) method. Cerebellum was used as a reference region. For the third study, the binding was measured only with the ITR method, and the results were compared to the baseline results. Studies showed that the average transient equilibrium time in the dorsal striatum (DSTR) was at 90 min for [F]fallypride and 30 min for [F]DMFP. The average BP for [F]fallypride was 14.4 in DSTR, 6.8 in ventral striatum (VSTR), 1.3 in substantia nigra/ventral tegmental area (SN/VTA), 1.4 in colliculi (COL), and 1.5 in central gray area. In the case of [F]DMFP, the average BP values were 2.2 in DSTR, 2.7 in VSTR, and 0.8 in SN/VTA. The haloperidol blockade showed detectable decrease in binding of both tracers in striatal regions with a faster displacement of [F]DMFP. No significant changes in BP of [F]fallypride due to the initial awake state of the animal were found, whereas BP of [F]DMFP was significantly higher in the awake state compared to baseline. We were able to demonstrate that dynamic PET using MicroPET Inveon allows quantification of both striatal and extrastriatal [F]fallypride binding in rats in vivo. Quantification of the striatal regions could be achieved with [F]DMFP. Synapse 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of 18F-5-OH-FPPAT, and the newer 18F-5-OH-FHXPAT and 18F-7-OH-FHXPAT. Syntheses of 18F-5-OH-FHXPAT and 18F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74-111 kBq/cc). Competition with dopamine (1-100 nM) and Gpp(NH)p (10-50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of 18F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with 18F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using 18F-7-OH-FHXPAT (2-37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10−2 min−1 for 18F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50-80% striatal binding with faster dissociation rates (5.0 × 10−2 min−1), suggesting HA-state binding of 18F-5-OH-FPPAT and 18F-5-OH-FHXPAT. Striatal binding of 18F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of 18F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor. [ABSTRACT FROM AUTHOR]

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 (0.015 mg kg−1) DST −22%, VST −29%; high-dose (1.88 mg kg−1) DST −58%, VST −77%, suggesting D3R/D2R displacement. BP 897 and NGB 2904 competed with 18F-fallypride in vitro, but unlike BP 897, NGB 2904 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. Synapse 69:577-591, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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 agonist, 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 69:96-98, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]