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Purpose: [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. Procedures: [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 [F]-FEPPA binding (high-affinity binder (HAB) and low-affinity binder (LAB)), was performed. Results: 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. Conclusions: [F]-FEPPA radiation dose is consistent with other F-labeled radioligands and the Ala147Thr genotype agreed with [F]-FEPPA distribution. [ABSTRACT FROM AUTHOR]

Purpose: We measured the whole-body distribution of IV-injected [C]GSK215083, a new 5-HT antagonist PET tracer, as a function of time in adult subjects, in order to determine the radiation exposure. Procedures: After injection with a single bolus of [C]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. Results: The mean effective dose averaged over both males and females (±standard 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). Conclusion: The estimated radiation dose for [C]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, [C]GSK215083 may be used for multiple PET scans in the same subject. [ABSTRACT FROM AUTHOR]

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 COV<10%, across high-uptake ROIs. The excellent identifiability of VT 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. [ABSTRACT FROM AUTHOR]

Imaging the competition between D2/3 radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D2 receptor exists in a high (D2high) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D2high only. [11C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [11C]-(+)-PHNO is expected to bind preferentially to D2high, 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. [11C]-(+)-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 [11C]-(+)-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 D2/3 agonist radioligand in humans. [11C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D2/3 antagonist radioligands.Neuropsychopharmacology (2008) 33, 279–289; doi:10.1038/sj.npp.1301400; published online 4 April 2007 [ABSTRACT FROM AUTHOR]

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.Neuropsychopharmacology (2007) 32, 1209–1215. doi:10.1038/sj.npp.1301242; published online 1 November 2006 [ABSTRACT FROM AUTHOR]

Abstract: 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: [11C]-WAY 100635, [11C]-raclopride and [11C]-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. [Copyright &y& Elsevier]