Dustin Wooten

Amyloid burden and neural function in people at risk for Alzheimer's Disease

To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimers Disease (AD), we used multimodal imaging with [C-11]Pittsburgh compound B positron emission tomography, [F-18]fluorodeoxyglucose, positron emission tomography , and magnetic resonance imaging, together with cognitive measurement in 201 subjects (mean age, 60.1 years; range, 46-73 years) from the Wisconsin Registry for Alzheimers Prevention. Using a qualitative rating, 18% of the samples were strongly positive Beta-amyloid (Aβ+), 41% indeterminate (Aβi), and 41% negative (Aβ-). Aβ+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aβ- group, Aβ+ and Aβi participants had increased glucose metabolism in the bilateral thalamus; Aβ+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aβ+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aβ- group, and no areas of significant atrophy. Cognitive performance and self report cognitive and affective symptoms did not differ between groups. Amyloid burden can be identified in adults at a mean age of 60 years and is accompanied by glucometabolic increases in specific areas, but not atrophy or cognitive loss. This asymptomatic stage may be an opportune window for intervention to prevent progression to symptomatic AD.

In Vivo Kinetics of (F-18)MEFWAY: A Comparison With (C-11)WAY100635 and (F-18)MPPF in the Nonhuman Primate

[F‐18]Mefway was developed to provide an F‐18 labeled positron emission tomography (PET) neuroligand with high affinity for the serotonin 5‐HT1A receptor to improve the in vivo assessment of the 5‐HT1A system. The goal of this work was to compare the in vivo kinetics of [F‐18]mefway, [F‐18]MPPF, and [C‐11]WAY100635 in the rhesus monkey. Methods: Each of four monkeys were given bolus injections of [F‐18]mefway, [C‐11]WAY100635, and [F‐18]MPPF and scans were acquired with a microPET P4 scanner. Arterial blood was sampled to assay parent compound throughout the time course of the PET experiment. Time activity curves were extracted in the high 5‐HT1A binding areas of the anterior cingulate cortex (ACG), mesial temporal cortex, raphe nuclei, and insula cortex. Time activity curves were also extracted in the cerebellum, which was used as a reference region. The in vivo kinetics of the radiotracers were compared based on the nondisplaceable distribution volume (VND) and binding potential (BPND). Results: At 30 min, the fraction of radioactivity in the plasma due to parent compound was 19%, 28%, and 29% and cleared from the arterial plasma at rates of 0.0031, 0.0078, and 0.0069 (min−1) ([F‐18]mefway, [F‐18]MPPF, [C‐11]WAY100635). The BPND in the brain regions were mesial temporal cortex: 7.4 ± 0.6, 3.1 ± 0.4, 7.0 ± 1.2, ACG: 7.2 ± 1.2, 2.1 ± 0.2, 7.9 ± 1.2; raphe nuclei: 3.7 ± 0.6, 1.3 ± 0.3, 3.3 ± 0.7; and insula cortex: 4.2 ± 0.6, 1.2 ± 0.1, 4.7 ± 1.0 for [F‐18]mefway, [F‐18]MPPF, and [C‐11]WAY100635 respectively. Conclusions: In the rhesus monkey, [F‐18]mefway has similar in vivo kinetics to [C‐11]WAY100635 and yields greater than 2‐fold higher BPND than [F‐18]MPPF. These properties make [F‐18]mefway a promising radiotracer for 5‐HT1A assay, providing higher counting statistics and a greater dynamic range in BPND. Synapse, 2011.

Pharmacokinetic Evaluation of the Tau PET Radiotracer 18F-T807 (18F-AV-1451) in Human Subjects

18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region–based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region–based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion: 18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80–100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.

Specific α4β2 Nicotinic Acetylcholine Receptor Binding of [F-18]Nifene in the Rhesus Monkey

[F‐18]Nifene is a PET radioligand developed to image α4β2* nicotinic acetylcholine receptors (nAChR) in the brain. This work assesses the in vivo binding and imaging characteristics of [F‐18]nifene in rhesus monkeys for the development of PET experiments examining nAChR binding.

PET Imaging of α4β2* Nicotinic Acetylcholine Receptors: Quantitative Analysis of 18F-Nifene Kinetics in the Nonhuman Primate

The PET radioligand 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) is an α4β2* nicotinic acetylcholine receptor (nAChR) agonist developed to provide accelerated in vivo equilibrium compared with existing α4β2* radioligands. The goal of this work was to analyze the in vivo kinetic properties of 18F-nifene with both kinetic modeling and graphical analysis techniques. Methods: Dynamic PET experiments were performed on 4 rhesus monkeys (female; age range, 9–13 y) using a small-animal PET scanner. Studies began with a high-specific-activity 18F-nifene injection, followed by a coinjection of 18F-nifene and unlabeled nifene at 60 min. Sampling of arterial blood with metabolite analysis was performed throughout the experiment to provide a parent radioligand input function. In vivo kinetics were characterized with both a 1-tissue-compartment model (1TCM) and a 2-tissue-compartment model, Logan graphical methods (both with and without blood sampling), and the multilinear reference tissue model. Total distribution volumes and nondisplaceable binding potentials (BPND) were used to compare regional binding of 18F-nifene. Regions examined include the anteroventral thalamus, lateral geniculate body, frontal cortex, subiculum, and cerebellum. Results: The rapid uptake and binding of 18F-nifene in nAChR-rich regions of the brain was appropriately modeled using the 1TCM. No evidence for specific binding of 18F-nifene in the cerebellum was detected on the basis of the coinjection studies, suggesting the suitability of the cerebellum as a reference region. Total distribution volumes in the cerebellum were 6.91 ± 0.61 mL/cm3. BPND values calculated with the 1TCM were 1.60 ± 0.17, 1.35 ± 0.16, 0.26 ± 0.08, and 0.30 ± 0.07 in the anteroventral thalamus, lateral geniculate body, frontal cortex, and subiculum, respectively. For all brain regions, there was a less than 0.04 absolute difference in the average BPND values calculated with each of the 1TCM, multilinear reference tissue model, and Logan methods. Conclusion: The fast kinetic properties and specific regional binding of 18F-nifene promote extension of the radioligand into preclinical animal models and human subjects.

Serotonin Transporter Genotype Affects Serotonin 5-HT1A Binding in Primates

Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding using in vivo imaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor binding at the 5-HT1A receptor site has been reported in humans, suggesting the 5-HTTLPR polymorphism may play a role in serotonin (5-HT) function. Rhesus monkeys possess a 5-HTTLPR length polymorphism similar to humans and serve as an excellent model for studying the effects of this orthologous genetic variation on behaviors and neurochemical functions related to the 5-HT system. In this study, PET imaging of [18F]mefway was performed on 58 rhesus monkeys (33 l/l, 25 s-carriers) to examine the relation between 5-HT1A receptor-specific binding and 5-HTTLPR genotypes. Significantly lower 5-HT1A binding was found in s-carrier subjects throughout both cortical brain regions and the raphe nuclei. These results demonstrate that the underlying 5-HT neurochemical system is influenced by this functional polymorphism and illustrate the strong potential for extending the nonhuman primate model into investigating the role of this genetic variant on behavior and gene–environment interactions.

An In Vivo Comparison of Cis- and Trans- [18F]Mefway in the Nonhuman Primate

INTRODUCTION [(18)F]Mefway is a serotonin 5-HT(1A) PET radiotracer with high specificity and favorable in vivo imaging properties. The chemical structure of [(18)F]mefway permits (18)F labeling in either the cis or trans positions at the 4-cyclohexyl site. We have previously reported on the in vivo kinetics of trans-[(18)F]mefway in the nonhuman primate. In this work, we compare the in vivo binding of cis-[(18)F]mefway and trans-[(18)F]mefway to evaluate the properties of cis-[(18)F]mefway for 5-HT(1A) PET imaging. METHODS The cis- and trans-[(18)F]mefway tracers were synthesized via nucleophilic substitution with their respective tosyl precursors. Two monkeys (one male, one female) were given bolus injections of both cis- and trans-labeled [(18)F]mefway in separate experiments. Dynamic scans were acquired for 90 min with a microPET P4 scanner. Time-activity curves were extracted in the areas of the mesial temporal cortex (MTC), anterior cingulate gyrus (aCG), insular cortex (IC), raphe nuclei (RN) and cerebellum (CB). The in vivo behavior of the radiotracers was compared based upon the nondisplaceable binding potential (BP(ND)) using the CB as a reference region. RESULTS Averaged over the two subjects, BP(ND) values were as follows: MTC: 7.7, 0.58; aCG: 4.95, 0.32; IC: 3.27, 0.2; and RN: 3.05, 0.13, for trans-[(18)F]mefway and cis-[(18)F]mefway, respectively. CONCLUSION The cis-labeled [(18)F]mefway tracer has low specific binding throughout the 5-HT(1A) regions of the brain compared to trans-[(18)F]mefway, suggesting that the target-to-background binding of cis-[(18)F]mefway may limit its use for in vivo assessment of 5-HT(1A) binding.

Measuring α4β2∗ Nicotinic Acetylcholine Receptor Density in Vivo with [18F]nifene PET in the Nonhuman Primate

[18F]Nifene is an agonist PET radioligand developed to image α4β2∗ nicotinic acetylcholine receptors (nAChRs). This work aims to quantify the receptor density (Bmax) of α4β2∗ nAChRs and the in vivo (apparent) dissociation constant (KDapp) of [18F]nifene. Multiple-injection [18F]nifene experiments with varying cold nifene masses were conducted on four rhesus monkeys with a microPET P4 scanner. Compartment modeling techniques were used to estimate regional Bmax values and a global value of KDapp. The fast kinetic properties of [18F]nifene also permitted alternative estimates of Bmax and KDapp at transient equilibrium with the same experimental data using Scatchard-like methodologies. Averaged across subjects, the compartment modeling analysis yielded Bmax values of 4.8 ± 1.4, 4.3 ±1.0, 1.2 ± 0.4, and 1.2 ± 0.3 pmol/mL in the regions of antereoventral thalamus, lateral geniculate, frontal cortex, and subiculum, respectively. The KDapp of nifene was 2.4 ± 0.3 pmol/mL. The Scatchard analysis based on graphical evaluation of the data after transient equilibrium yielded Bmax estimations comparable to the modeling results with a positive bias of 28%. These findings show the utility of [18F]nifene for measuring α4β2∗ nAChR Bmax in vivo in the rhesus monkey with a single PET experiment.

First-in-Human Evaluation of 18F-Mefway, a PET Radioligand Specific to Serotonin-1A Receptors

The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A–specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-18F-fluoromethylcyclohexane)carboxamide (18F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of 18F-mefway in humans. Methods: Dynamic 18F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22–38 y). Scans were initiated with the injection of 192–204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of 18F-mefway. To examine the test–retest variability of 18F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone. Results: 18F-mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4–0.9 at 120 min. Rapid metabolism of 18F-mefway was observed, with no detected 18F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7–1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test–retest variability was 8%. No evidence of radioactivity uptake in bone was observed. Conclusion: 18F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make 18F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.

Changes in the α4β2* nicotinic acetylcholine system during chronic controlled alcohol exposure in nonhuman primates

BACKGROUND The precise nature of modifications to the nicotinic acetylcholine receptor (nAChR) system in response to chronic ethanol exposure is poorly understood. The present work used PET imaging to assay α4β2* nAChR binding levels of eight rhesus monkeys before and during controlled chronic ethanol intake. METHODS [(18)F]Nifene PET scans were conducted prior to alcohol exposure, and then again after at least 8 months controlled ethanol exposure, including 6 months at 1.5 g/kg/day following a dose escalation period. Receptor binding levels were quantified with binding potentials (BPND) using the cerebellum as a reference region. Alcohol self-administration was assessed as average daily alcohol intake during a 2 month free drinking period immediately following controlled alcohol. RESULTS Significant decreases in α4β2* nAChR binding were observed in both frontal and insular cortex in response to chronic ethanol exposure. During chronic alcohol exposure, BPND in the lateral geniculate region correlated positively with the amount of alcohol consumed during free drinking. CONCLUSIONS The observed decreases in nAChR availability following chronic alcohol consumption suggest alterations to this receptor system in response to repeated alcohol administration, making this an important target for further study in alcohol abuse and alcohol and nicotine codependence.