Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors.

UNLABELLED: PET with selective adenosine 2A receptor (A2A) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A2A. The aim of this study was to describe the first in vivo evaluation of (18)F-MNI-444, a novel PET radiotracer for imaging A2A, in healthy human subjects. METHODS: Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. RESULTS: After intravenous bolus injection, (18)F-MNI-444 rapidly entered the brain and displayed a distribution consistent with known A2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A2A-rich regions, with an average test-retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. CONCLUSION: (18)F-MNI-444 is a useful PET radiotracer for imaging A2A in the human brain. The superior in vivo brain kinetic properties of (18)F-MNI-444, compared with previously developed A2A radiotracers, provide the opportunity to foster global use of in vivo A2A PET imaging in neuroscience research.

Adenosine 2A receptor occupancy by tozadenant and preladenant in rhesus monkeys.

UNLABELLED: Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A(2A)) receptors facilitates dopamine D(2) receptor function. In phase 2 clinical trials, A(2A) antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A(2A) PET radiotracer, (18)F-MNI-444, and used it to investigate the relationship between plasma levels and A(2A) occupancy by preladenant and tozadenant in nonhuman primates (NHP). METHODS: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical analysis) and reference-region-based (simplified reference tissue model and noninvasive Logan graphical analysis) methods. Whole-body PET images were acquired for radiation dosimetry estimates. Human pharmacokinetic parameters for tozadenant and preladenant were used to predict A(2A) occupancy in humans, based on median effective concentration (EC(50)) values estimated from the NHP PET measurements. RESULTS: (18)F-MNI-444 regional uptake was consistent with A(2A) receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A(2A) PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A(2A) receptor occupancy in humans. CONCLUSION: (18)F-MNI-444 appears to be a better PET radiotracer for A(2A) imaging than currently available radiotracers. Assuming that EC(50) in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A(2A) receptor occupancy than preladenant in humans at clinically tested doses.

The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [¹¹C]NNC112.

D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [¹¹C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF versus controls comparison. Furthermore, in the DF group, DF interval correlated positively with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be corrected and normalized by chronic antipsychotic treatment.

Biodistribution and radiation dosimetry of the serotonin 5-HT6 ligand [¹¹C]GSK215083 determined from human whole-body PET.

PURPOSE: 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. PROCEDURES: 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. RESULTS: 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). CONCLUSION: 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.

Biodistribution and radiation dosimetry of the glycine transporter-1 ligand 11C-GSK931145 determined from primate and human whole-body PET.

PURPOSE: (11)C-GSK931145 is a novel radioligand suitable for imaging the glycine transporter 1 (GlyT-1) in brain. In the present study, human dosimetry is estimated from baboon and human biodistribution data. PROCEDURES: Three baboons and eight healthy human volunteers underwent whole-body positron emission tomography (PET) scans. Human dosimetry was estimated using three different region-of-interest (ROI) delineation methods that ranged in their complexity and execution time: ROIs drawn on anterior-posterior compressed PET images, on subsamples of the organs, and covering the whole-organ. Residence times for each organ were calculated as the area under the time-activity curves divided by the injected activity. Radiation dose estimates were calculated from organ residence times using the OLINDA/EXM software package. RESULTS: The overall distribution of activity was similar in baboons and humans. Early scans presented high activity in the liver, and moderate activity in the lungs and kidneys. The principal route of clearance was intestinal and no urinary excretion was observed. The limiting organ with the highest radiation-absorbed dose was the liver. The mean effective dose in humans was 4.02 µSv/MBq (male phantom) and 4.95 µSv/MBq (female phantom) (ROIs drawn on subsamples of the organs). The human effective dose estimated from baboon data was ~15% larger than the effective dose estimated from human data. CONCLUSION: Human PET imaging of the glycine transporter-1 with (11)C-GSK931145 results in a moderate effective human radiation dose, which allows for multiple PET examinations in the same individual. Among the three methods compared to delineate ROIs, the organ subsampling method shows the best balance between quantitative accuracy and practical application.

Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.

CONTEXT: A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D(2) receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D(2) receptors is responsible for the antipsychotic action of D(2) receptor antagonists. OBJECTIVE: To localize dopaminergic hyperactivity within the striatum in schizophrenia. DESIGN: Case-control study. SETTING: Inpatient research unit. PARTICIPANTS: Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight. MAIN OUTCOME MEASURES: Percentage change in dopamine D(2) receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11-labeled raclopride before and during pharmacologically induced dopamine depletion. RESULTS: In the associative striatum, acute dopamine depletion resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum. CONCLUSIONS: These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

Biodistribution and radiation dosimetry of the dopamine D2 ligand 11C-raclopride determined from human whole-body PET.

UNLABELLED: Whole-body radiation dosimetry of 11C-raclopride was performed in healthy human volunteers. METHODS: Subjects (n = 6) were scanned with PET. Subjects received single-bolus injections of 11C-raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy-6-methoxybenzamide) (533 +/- 104 MBq) and were scanned for approximately 110 min with a 2-dimensional whole-body protocol. Regions of interest were placed over all visually identifiable organs and time-activity curves were generated. Residence times were computed as the area under the curve of the time-activity curves, normalized to injected activities and standard values of organ volumes. Absorbed doses were computed according to the MIRD schema with MIRDOSE3.1 software. RESULTS: Organs with the highest radiation burden were gallbladder wall, small intestine, liver, and urinary bladder wall. CONCLUSION: On the basis of the estimated absorbed dose, the maximum allowable single study dose under U.S. federal regulations for studies performed under Radiation Drug Research Committee is 1.58 GBq (42.8 mCi). This is still considerably higher than the doses of 11C-raclopride commonly used in research PET (370-555 MBq).