Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET:  Dopamine Movies of Cigarette Smoking

We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute ...

University of California, Irvine

We have developed a nonparametric approach to the analysis of dynamic positron emission tomography (PET) data for extracting temporal characteristics of the change in endogenous neurotransmitter concentration in the brain. An algebraic method based on singular value decomposition (SVD) was applied to simulated data under both rest (neurotransmitter at baseline) and activated (transient neurotransmitter release) conditions. The resulting signals are related to the integral of the change in free neurotransmitter concentration in the tissue. Therefore, a specially designed minimum mean-square error (MMSE) filter must be applied to the signals to recover the desired temporal pattern of neurotransmitter change. To test the method, we simulated sets of realistic time activity curves representing uptake of [11C]raclopride, a dopamine (DA) receptor antagonist, in brain regions, under baseline and dopamine-release conditions. Our tests considered two scenarios: 1) a spatially homogeneous pattern with all voxels in the activated state presenting an identical DA signal; 2) a spatially heterogeneous pattern in which different DA signals were contained in different families of voxels. In the first case, we demonstrated that the timing of a single DA peak can be accurately identified to within 1 min and that two distinct neurotransmitter peaks can be distinguished. In the second case, separate peaks of activation separated by as little as 5 min can be distinguished. A decrease in blood flow during activation could not account for our findings. We applied the method to human PET data acquired with [11C]raclopride in the presence of transiently elevated DA due to intravenous (IV) alcohol. Our results for an area of the nucleus accumbens-a region relevant to alcohol consumption-agreed with a model-based method for estimating the DA response. SVD-based analysis of dynamic PET data promises a completely noninvasive and model-independent technique for determining the dynamics of a neurotransmitter response to cognitive or pharmacological stimuli. Our results indicate that the method is robust enough for application to voxel-by-voxel data.

Nonparametric extraction of transient changes in neurotransmitter concentration from dynamic PET data.

A dopaminergic response to alcohol in humans has not been demonstrated consistently with positron emission tomography (PET). We hypothesized that the effect of alcohol on striatal dopamine (DA) release may be anatomically heterogeneous between subjects. Our approach was to identify voxels that exhibited alcohol-induced DA responses within the striatum, and to determine the relationships between DA responses and alcohol-related behavior.

Heterogeneous effects of alcohol on dopamine release in the striatum: a PET study.

The mesolimbic dopamine (DA) system is implicated in the development and maintenance of alcohol drinking; however, the exact mechanisms by which DA regulates human alcohol consumption are unclear. This study assessed the distinct effects of alcohol-related cues and alcohol administration on striatal DA release in healthy humans.

When what you see isn't what you get: alcohol cues, alcohol administration, prediction error, and human striatal dopamine.

We evaluated the performance of an Inveon preclinical PET scanner (Siemens Medical Solutions), the latest MicroPET system. Spatial resolution was measured with a glass capillary tube (0.26 mm inside diameter, 0.29 mm wall thickness) filled with (18)F solution. Transaxial and axial resolutions were measured with the source placed parallel and perpendicular to the axis of the scanner. The sensitivity of the scanner was measured with a (22)Na point source, placed on the animal bed and positioned at different offsets from the center of the field of view (FOV), as well as at different energy and coincidence windows. The noise equivalent count rates (NECR) and the system scatter fraction were measured using rat-like (Phi = 60, L = 150 mm) and mouse-like (Phi = 25 mm, L = 70 mm) cylindrical phantoms. Line sources filled with high activity (18)F (>250 MBq) were inserted parallel to the axes of the phantoms (13.5 and 10 mm offset). For each phantom, list-mode data were collected over 24 h at 350-650 keV and 250-750 keV energy windows and 3.4 ns coincidence window. System scatter fraction was measured when the random event rates were below 1%. Performance phantoms consisting of cylinders with hot rod inserts filled with (18)F were imaged. In addition, we performed imaging studies that show the suitability of the Inveon scanner for imaging small structures such as those in mice with a variety of tracers. The radial, tangential and axial resolutions at the center of FOV were 1.46 mm, 1.49 and 1.15 mm, respectively. At a radial offset of 2 cm, the FWHM values were 1.73, 2.20 and 1.47 mm, respectively. At a coincidence window of 3.4 ns, the sensitivity was 5.75% for EW = 350-650 keV and 7.4% for EW = 250-750 keV. For an energy window of 350-650 keV, the peak NECR was 538 kcps at 131.4 MBq for the rat-like phantom, and 1734 kcps at 147.4 MBq for the mouse-like phantom. The system scatter fraction values were 0.22 for the rat phantom and 0.06 for the mouse phantom. The Inveon system presents high image resolution, low scatter fraction values and improved sensitivity and count rate performance.

Performance evaluation of an Inveon PET preclinical scanner.

In this study, we compared two different D(2/3) receptor ligands, [Â¹â¸F]fallypride and [Â¹â¸F]desmethoxyfallypride ([Â¹â¸F]DMFP) with respect to the duration of the scan, visualization of extrastriatal receptors, and binding potentials (BP(ND) ) 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 [Â¹â¸F]fallypride and with [Â¹â¸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 [Â¹â¸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-[Â¹â¸F]fallypride injection and 60-min post-[Â¹â¸F]DMFP. For the test-retest studies, BP(ND) 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 [Â¹â¸F]fallypride and 30 min for [Â¹â¸F]DMFP. The average BP(ND) for [Â¹â¸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 [Â¹â¸F]DMFP, the average BP(ND) 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 [Â¹â¸F]DMFP. No significant changes in BP(ND) of [Â¹â¸F]fallypride due to the initial awake state of the animal were found, whereas BP(ND) of [Â¹â¸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 [Â¹â¸F]fallypride binding in rats in vivo. Quantification of the striatal regions could be achieved with [Â¹â¸F]DMFP.

Striatal and extrastriatal microPET imaging of D2/D3 dopamine receptors in rat brain with [Â¹â¸F]fallypride and [Â¹â¸F]desmethoxyfallypride.

MicroPET imaging studies using (18)F-nifene, a new positron emission tomography (PET) radiotracer for nicotinic acetylcholinergic receptors (nAChR) Î±4Î²2 receptors in rats, have been carried out. Rats were imaged for 90 min after intravenous injection of (18)F-nifene (0.8 to 1 mCi), and binding potential (BP(ND)) was measured. (18)F-Nifene binding to thalamic and extrathalamic brain regions was consistent with the Î±4Î²2 nAChR distribution in the rat brain. Using the cerebellum as a reference, the values for the thalamus varied less than 5% (BP(ND) = 1.30, n = 3), confirming reproducibility of (18)F-nifene binding. (18)F-Nifene microPET imaging was also used to evaluate effects of nicotine in a group of Sprague-Dawley rats under isoflurane anesthesia. Nicotine challenge postadministration of (18)F-nifene demonstrated reversibility of (18)F-nifene binding in vivo. For Î±4Î²2 nAChR receptor occupancy (nAChR(OCC)), various doses of nicotine (0, 0.02, 0.1, 0.25, and 0.50 mg/kg nicotine free base) 15 min prior to (18)F-nifene were administered. Low-dose nicotine (0.02 mg) reached > 80% nAChR(OCC) while at higher doses (0.25 mg) > 90% nAChR(OCC) was measured. The small amount of (18)F-nifene binding with reference to the cerebellum affects an accurate evaluation of nAChR(OCC). Efforts are underway to identify alternate reference regions for (18)F-nifene microPET studies in rodents.

Evaluation of F-nifene binding to Î±4Î²2 nicotinic receptors in the rat brain using microPET imaging.

Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound Â¹â¸F-nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory-cognitive task. We first show negligible binding of Â¹â¸F-nifene in mice lacking the Î²2 nAChR subunit, consistent with previous findings that Â¹â¸F-nifene binds to Î±4Î²2* nAChRs. We then examined the distribution of Â¹â¸F-nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, Â¹â¸F-nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, Â¹â¸F-nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related Â¹â¸F-nifene binding in several forebrain regions to each animal's performance on an auditory-cued, active avoidance task. The strongest correlations with performance after 14 days training were found for Â¹â¸F-nifene binding in the temporal subcortical white matter, subiculum, and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory-cognitive function.

Nicotinic acetylcholine receptors in rat forebrain that bind Â¹â¸F-nifene: relating PET imaging, autoradiography, and behavior.

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 Î²3-adrenergic receptor-mediated 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 Î²3-adrenoceptor agonist) and measured by 18F-FDG PET/computed tomography [CT].

Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and &#946;3-adrenergic receptor activation.

[(18)F]Mefway is a novel radiotracer specific to the serotonin 5-HT1A receptor class. In preparation for using this tracer in humans, we have performed whole-body PET studies in mice to evaluate the biodistribution and dosimetry of [(18)F]Mefway.

Evaluation of [18F]Mefway biodistribution and dosimetry based on whole-body PET imaging of mice.

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 (18)F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous (18)F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before (18)F-FDG administration. To confirm the Î²-adrenergic effects, propranolol (Î²-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 (18)F-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 (18)F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average (18)F-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 (18)F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of Î²(3)-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 Î²(3)-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by (18)F-FDG PET/CT.

Targeting presynaptic norepinephrine transporter in brown adipose tissue: a novel imaging approach and potential treatment for diabetes and obesity.

[(18)F]Nifene is a novel radiotracer specific to the nicotinic acetylcholine Î±4Î²2 receptor class. In preparation for using this tracer in humans we have performed whole-body PET studies in mice to evaluate the in vivo biodistribution and dosimetry of [(18)F]Nifene.

Evaluation of [18F]Nifene biodistribution and dosimetry based on whole-body PET imaging of mice.

Serotonin 5-HT1A receptors have been investigated in various CNS disorders, including epilepsy, mood disorders, and neurodegeneration. [(18) F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[(18) F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [(18) F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies.

Cristian C. Constantinescu

Radiological Sciences

University of California, Irvine

Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking

Cristian C. Constantinescu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Radiological Sciences

University of California, Irvine

Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking

Radiological Sciences