Patrick J. Lao

The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer‐like neuropathology.

Deficient Import of Acetyl-CoA into the ER Lumen Causes Neurodegeneration and Propensity to Infections, Inflammation, and Cancer

The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the Nε-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.

In vivo comparison of tau radioligands 18F-THK-5351 and 18F-THK-5317

This study compared the in vivo imaging characteristics of tau PET ligands 18F-THK-5351 and 18F-THK-5317 in the context of Alzheimer disease (AD). Additionally, reference tissue distribution volume ratio (DVR) estimation methods and SUV ratio (SUVR) timing windows were evaluated to determine the optimal strategy for specific binding quantification. Methods: Twenty-eight subjects (mean age ± SD, 71 ± 7 y) underwent either dynamic 90-min 18F-THK-5317 or 18F-THK-5351 PET scans. Bland–Altman plots were used to compare the simplified reference tissue method, multilinear reference tissue method (MRTM2), and Logan reference tissue DVR estimates and to assess temporal stability of SUVR windows using cerebellar gray matter as a reference region. In vivo kinetics and DVR estimates were directly compared for 10 subjects who underwent both 18F-THK-5317 and 18F-THK-5351 PET scans. Results: THK-5351 exhibited faster cerebellar gray matter clearance, faster cortical white matter clearance, and higher DVR estimates in AD tau-associated regions of interest than THK-5317. The MRTM2 method produced the most reliable DVR estimates for both tracers, particularly when scan duration was shortened to 60 min. SUVR stability was observed 50–70 min after injection for both tracers. Parametric images revealed differences between MRTM2, Logan, and SUVR binding in white matter regions for THK-5317. Conclusion: THK-5317 and THK-5351 show promise for in vivo detection of AD tau. THK-5351 has more favorable pharmacokinetics and imaging characteristics than THK-5317.

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.

Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population

Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimers disease (AD).

PET imaging of acetylcholinesterase inhibitor‐induced effects on α4β2 nicotinic acetylcholine receptor binding

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimers disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo α4β2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The α4β2 nAChR‐specific radioligand [18F]nifene was used to examine the effects of 0.1–0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60‐min bolus‐infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [18F]nifene. Significant [18F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [18F]nifene in detecting increases in synaptic ACh induced by AChEIs. Synapse 67:882–886, 2013.

Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways

Nicotinic acetylcholinergic receptors (nAChRs) have been implicated in several brain disorders, including addiction, Parkinsons disease, Alzheimers disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [18F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.34 nM), hα3β2 (0.80 nM) and hα4β2 (0.83 nM) nAChR but weaker (27–219 nM) for hβ4 nAChR subtypes and 169 nM for hα7 nAChR. In functional assays, Nifene (100 μM) exhibited 14% agonist and >50% antagonist characteristics. In 14‐day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 μg/kg/day (278 μg/m2/day). In human PET studies, [18F]Nifene (185 MBq; <0.10 μg) was well tolerated with no adverse effects. Distribution volume ratios (DVR) of [18F]Nifene in white matter thalamic radiations were ∼1.6 (anterior) and ∼1.5 (superior longitudinal fasciculus). Habenula known to contain α3β2 nAChR exhibited low levels of [18F]Nifene binding while the red nucleus with α2β2 nAChR had DVR ∼1.6–1.7. Females had higher [18F]Nifene binding in all brain regions, with thalamus showing >15% than males. No significant aging effect was observed in [18F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18F]Nifene PET may be used to study α4β2* nAChRs in various CNS disorders and for translational research.

[18F]Nifene test-retest reproducibility in first-in-human imaging of α4β2* nicotinic acetylcholine receptors: LAO et al.

The aim of this study was to examine the suitability of [18 F]nifene, a novel α4β2* nicotinic acetylcholine receptor (nAChR) radiotracer, for in vivo brain imaging in a first‐in‐human study. Methods: Eight healthy subjects (4 M,4 F;21–69,44 ± 21 yrs) underwent a [18F]nifene positron emission tomography scan (200 ± 3.7 MBq), and seven underwent a second scan within 58 ± 31 days. Regional estimates of DVR were measured using the multilinear reference tissue model (MRTM2) with the corpus callosum as reference region. DVR reproducibility was evaluated with test–retest variability (TRV) and intraclass correlation coefficient (ICC). Results: The DVR ranged from 1.3 to 2.5 across brain regions with a TRV of 0–7%, and did not demonstrate a systematic difference between test and retest. The ICCs ranged from 0.2 to 0.9. DVR estimates were stable after 40 min. Conclusion: The binding profile and tracer kinetics of [18F]nifene make it a promising α4β2* nAChR radiotracer for scientific research in humans, with reliable DVR test–retest reproducibility.

Human biodistribution and dosimetry of [18F]nifene, an α4β2* nicotinic acetylcholine receptor PET tracer

INTRODUCTION The α4β2* nicotinic acetylcholine receptor (nAChR) system is implicated in many neuropsychiatric pathologies. [18F]Nifene is a positron emission tomography (PET) ligand that has shown promise for in vivo imaging of the α4β2* nAChR system in preclinical models and humans. This work establishes the radiation burden associated with [18F]nifene PET scans in humans. METHODS Four human subjects (2M, 2F) underwent whole-body PET/CT scans to determine the human biodistribution of [18F]nifene. Source organs were identified and time-activity-curves (TACs) were extracted from the PET time-series. Dose estimates were calculated for each subject using OLINDA/EXM v1.1. RESULTS [18F]Nifene was well tolerated by all subjects with no adverse events reported. The mean whole-body effective dose was 28.4±3.8 mSv/MBq without bladder voiding, and 22.6±1.9 mSv/MBq with hourly micturition. The urinary bladder radiation dose limited the maximum injected dose for a single scan to 278 MBq without urinary bladder voiding, and 519 MBq with hourly voiding. CONCLUSIONS [18F]Nifene is a safe PET radioligand for imaging the α4β2* nAChR system in humans. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE This works presents human internal dosimetry for [18F]nifene in humans for the first time. These results facilitate safe development of future [18F]nifene studies to image the α4β2* nAChR system in humans.