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Using PET, we measured the whole-body distribution of 11C-(+)-PHNO (11C-(+)-4-propyl-9-hydroxynaphthoxazine), a D2/3 agonist, as a function of time in adult subjects in order to determine the internal radiation dose. Methods: PET whole-body data were acquired after the injection of 11C-(+)-PHNO (∼360 MBq) in 6 healthy subjects (3 male and 3 female). The PET acquisition duration was a maximum of 112.5 min, and 9 discrete time frames were obtained. After reconstruction of the emission data, 6 organs were identified in the images as exhibiting uptake above background levels. Regions of interest were delineated on these organs, and time–activity curves were generated. The time–activity curve data were corrected for the injected activity, specific organ density, and volume, from which normalized accumulated activities (previously known as residence times) were calculated. The normalized accumulated activities were then used with the software code OLINDA/EXM 1.1 to calculate the internal doses for the standard adult male and female models. Results: The mean effective dose was estimated to be 4.5 ± 0.3 μSv/MBq when all subjects were included and the male model was applied for the dosimetry calculation, and the mean effective dose was estimated to be 5.2 ± 0.2 μSv/MBq when the females were considered separately and the female model was applied for the calculation. The organ receiving the highest dose was the liver (17.9 ± 3.9 μSv/MBq), followed by the kidneys (14.3 ± 3.6 μSv/MBq) and the urinary bladder wall (13.5 ± 3.7 μSv/MBq). Conclusion: The estimated radiation doses for 11C-(+)-PHNO are similar to those reported for other radiotracers labeled with 11C. 11C-(+)-PHNO may be used for multiple PET scans in the same subject and remain within regulatory guidelines.

This article describes the kinetic modeling of [18F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one-tissue model. Estimates of total distribution volume ( VT), specific distribution volume ( VS), and binding potential ( BPND) demonstrated very good identifiability (based on coefficient of variation ( COV)) for all the regions of interest (ROIs) in the gray matter ( COV VT < 7%, COV VS < 8%, COV BPND < 11%). Reduction of the length of the scan to 2 hours is feasible as VS and VT showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of VT and VS was still very good with COVT values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of VT as an appropriate and feasible outcome measure for [18F]-FEPPA.

The D(2) receptors exist in either the high‐ or low‐affinity state with respect to agonists, and while agonists bind preferentially to the high‐affinity state, antagonists do not distinguish between the two states. [(11)C]‐(+)‐PHNO is a PET D(2) agonist radioligand and therefore provides a preferential measure of the D(2) (high) receptors. In contrast, [(11)C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D(2) high‐ and low‐affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [(11)C]‐(+)‐PHNO and [(11)C]raclopride in volunteers using a within‐subject design. Both radioligands accumulated in brain areas rich in D(2)/D(3)‐receptors. However, [(11)C]‐(+)‐PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [(11)C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [(11)C]raclopride, equal in the ventral‐striatum (3.4 vs. 3.3), and higher in the globus pallidus for [(11)C]‐(+)‐PHNO (1.8 vs. 3.3). Moreover [(11)C]‐(+)‐PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [(11)C]‐(+)‐PHNO in the globus pallidus and ventral‐striatum could be the presence of a greater proportion of high‐ vs. low‐affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D(3)‐over‐D(2) with [(11)C]‐(+)‐PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease. Hum Brain Mapp 2008. © 2007 Wiley‐Liss, Inc.

1993 Objectives To determine by a national survey: 1) the frequency of detection by public screening facilities of radioactivity in patients (pts) who had been treated with 131I for differentiated thyroid cancer (DTC), 2) the types and frequency of the various public facilities where pts were detected, and 3) the management of these pts by the security personnel. Methods Data were tabulated from a Thyroid Cancer Survivors Association, Inc. (ThyCa) website survey from November 2013 to December 2013 and was emailed to ~30,000 associates of ThyCa. Answers were tabulated of respondents (rpds) who reported that s/he 1) was >18 yo, 2) had at least one tx of 131I, and 3) was responding for his/her last 131I tx. The study was approved by the IRB. Results Of 334 rpds, 6.9% (23) attempted to pass through a public facility security checkpoint. Of these 23 pts all were detected and the detections occurred in an airport (7), border crossing (7), government building (3), shopping mall (3), train station (2), and steel recycling plant (1). The security personnel questioned 19 rpds, released 14 rpds without change in travel plans, rescanned 9 rpds, released 1 rpd with change in travel plans, and denied passage in 1 rpd. Security personnel verified the rpd’s 131I tx by examining an official document from the treating physician that was provided by 14 rpds, calling the treating facility regarding 3 rspds, and operating radiation detectors to identify the type and source of radiation in 2 rspds. Security personnel did not verify 131I tx in 4 rspds. Conclusions Public detection of radioactivity after 131I tx is infrequent, occurring in only 6.9% of respondents. Although airports and border crossings accounted for 61% of the sites of detection, the number of detected respondents was very low, and further respondents of the survey continue to be collected.

[(18)F]-FEPPA is a translocator protein (18 kDa, TSPO) positron emission tomography (PET) radiotracer. Radiation dosimetry was estimated from the whole body biodistribution, taking into consideration TSPO rs6971 (Ala147Thr) polymorphism.[(18)F]-FEPPA whole body PET scans were acquired for six healthy subjects. Time-activity curves were generated from regions of interest of nine organs, from which normalized accumulated activities were calculated and thus internal dose, using OLINDA/EXM 1.1. Genotyping of rs6971, associated with high- and low-affinity [(18)F]-FEPPA binding (high-affinity binder (HAB) and low-affinity binder (LAB)), was performed.Five subjects exhibited the C/C (HAB) allele, and the other carried the minor allele T/T (LAB). The LAB whole body biodistribution showed highest radioactivity accumulation in bladder, whereas in HABs, the spleen received the highest dose. The effective dose of the single LAB (16.3 μSv/MBq) was 23 % less than the mean of the HABs (21.0 ± 2.9 μSv/MBq). When including all subjects, the effective dose was 20.2 ± 3.0 μSv/MBq.[(18)F]-FEPPA radiation dose is consistent with other (18)F-labeled radioligands and the Ala147Thr genotype agreed with [(18)F]-FEPPA distribution.

We measured the whole-body distribution of IV-injected [¹¹C]GSK215083, a new 5-HT₆ antagonist PET tracer, as a function of time in adult subjects, in order to determine the radiation exposure.After injection with a single bolus of [¹¹C]GSK215083 (range 330-367 MBq; mean 346 MBq), PET emission data were acquired for approximately 120 min in six subjects (three males and three females). Five organs were identified as exhibiting uptake above background. For these, regions of interest were delineated on emission images, and time-activity curves (TAC) generated. Residence times were calculated as the area under the curve of the TAC, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using the computer program OLINDA/EXM 1.0.The mean effective dose averaged over both males and females (deviation) was estimated to be 7.7 ± 1.0 μSv/MBq (male 7.0 ± 0.4; female 8.5 ± 0.6). For the effective dose equivalent, the corresponding values are 7.8 ± 1.2 μSv/MBq (male 6.8 ± 0.5; female 8.9 ± 0.1). The organ receiving the highest dose was the lung, with an average equivalent dose of 25.6 ± 6.9 μSv/MBq (male 20.8 ± 5.6; female 30.4 ± 4.4).The estimated radiation dose for [¹¹C]GSK215083 is consistent with those for other neuroreceptor ligands labeled with carbon-11. The somewhat higher dose estimate for females compared to males may reflect the difference in observed residence times and representative differences in the male and female phantoms used for dosimetry calculations. Based on conventionally accepted dose limits, [¹¹C]GSK215083 may be used for multiple PET scans in the same subject.

TO THE EDITOR: 11C-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is a new PET ligand developed by our group. Binding assays show that (+)-PHNO displays high affinity and selectivity for the D2 receptor ( [1][1] ). Recently, it has been noted that 11C-(+)-PHNO has a preferential affinity and

OBJECTIVE: The pharmacokinetic and pharmacodynamic profile of the immediate-release (IR) formulation of quetiapine is characterized by a rapid peak in plasma level and striatal dopamine D(2) receptor occupancy, followed by a rapid decrease to baseline levels, necessitating the use of twice-daily dosing. An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D(2) receptor binding between the IR and XR formulations. METHOD: In this open-label, crossover positron emission tomography study using [(11)C]-raclopride, we compared the central D(2) receptor binding potential at expected peak and trough plasma levels using equivalent daily doses of the IR and XR formulations (300, 600, and 800 mg/day) in 12 subjects. Data were collected from April 2002 to May 2003. RESULTS: The mean plasma level of quetiapine at trough was significantly lower than that at peak for all dose groups of both formulations except for IR 300 and 800 mg (all p values < .05), while the mean plasma level did not differ significantly between formulations at trough and peak. The mean occupancy at peak was significantly higher than that at trough for all dose groups other than IR 800 mg/day (all p values < .05) and did not differ significantly between formulations at trough and peak. CONCLUSION: Once-daily dosing of the XR formulation gives peak and trough plasma levels and central D(2) receptor occupancy comparable to twice-daily dosing of the IR formulation. These data should be considered while determining equivalent doses, as well as switching strategies.

Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia., peer-reviewed

Manual drawing of regions of interest (ROIs) on brain positron emission tomography (PET) images is labour intensive and subject to intra- and inter-individual variations. To standardize analysis and improve the reproducibility of PET measures, we have developed image analysis software for automated quantification of PET data. The method is based on the individualization of a set of standard ROIs using a magnetic resonance (MR) image co-registered with the PET image. To evaluate the performance of this automated method, the software-based quantification has been compared with conventional manual quantification of PET images obtained using three different PET radiotracers: [ 11 C]-WAY 100635, [ 11 C]-raclopride and [ 11 C]-DASB. Our results show that binding potential estimates obtained using the automated method correlate highly with those obtained by trained raters using manual delineation of ROIs for frontal and temporal cortex, thalamus, and striatum (global intraclass correlation coefficient > 0.8). For the three radioligands, the software yields time–activity data that are similar (within 8%) to those obtained by manual quantification, eliminates investigator-dependent variability, considerably shortens the time required for analysis and thus provides an alternative method for accurate quantification of PET data.