Sandeep S.V. Golla

Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients.

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([18F] DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [18F]DPA-714 binding in healthy subjects and Alzheimers disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [18F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [18F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [18F]DPA-714 cannot be used for separating individual AD patients from heathy subjects, but further studies including TSPO binding status are needed to substantiate these findings.

Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man

[11C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N′-(3-[11C]methoxy-phenyl)-N′-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [11C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [11C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [11C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [11C]GMOM could be used for quantification of N-methyl-d-aspartate receptors.

Preclinical evaluation of [18F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

INTRODUCTION The present study was designed to assess whether [(18)F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([(18)F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). METHODS Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. RESULTS PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VT of [(18)F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. CONCLUSIONS PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [(18)F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.

Parametric Binding Images of the TSPO Ligand 18F-DPA-714

18F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of 18F-DPA-714 binding. Methods: Ninety-minute dynamic 18F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input–based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images. Results: Plasma-input Logan analysis (r2 = 0.99; slope, 0.88) and spectral analysis (r2 = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r2 = 0.83; slope, 0.95) and reference Logan analysis (r2 = 0.88; slope, 1.01) correlated well with nonlinear regression–based estimates. Conclusion: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of 18F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.

[18F]AV1451 PET IN RELATION TO ATROPHY ACROSS THE ALZHEIMER’S DISEASE SPECTRUM

P2-359 RELATION NETWORKS OF NEURODEGENERATION INALZHEIMER’S DISEASE SPECTRUM: TAU, AMYLOID, AND CORTICAL ATROPHY Jeong-Hyeon Shin, Sang Won Seo, Jee Hoon Roh, Minyoung Oh, Jungsu S. S. Oh, Seung Jun Oh, Jae Seung Kim, Joon-Kyung Seong, Korea University, Seoul, South Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Contact e-mail: sjhtom@naver.com

PARAMETRIC IMAGING OF TAU LOAD IN ALZHEIMER’S PATIENTS AND CONTROLS USING FLORTAUCIPIR

P4-235 PARAMETRIC IMAGING OF TAU LOAD IN ALZHEIMER’S PATIENTS ANDCONTROLS USING FLORTAUCIPIR Emma E. Wolters, Sandeep S. V. Golla, Tessa Timmers, Rik Ossenkoppele, Colin Groot, Chris W. J. van der Weijden, Sander C. J. Verfaillie, Philip Scheltens, Wiesje M. van der Flier, Lothar A. Schwarte, Mark A. Mintun, Michael D. Devous, Sr., Robert C. Schuit, Albert D. Windhorst, Adriaan A. Lammertsma, Ronald Boellaard, Bart N. M. van Berckel, Maqsood M. Yaqub, Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center, Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, Netherlands; Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands; Department of Anesthesiology, VU University Medical Center, Amsterdam, Netherlands; Avid Radiopharmaceuticals, Philadelphia, PA, USA; University Medical Center Groningen, Groningen, Netherlands. Contact e-mail: ee.wolters@vumc.nl

Measurement of absolute cerebral blood flow during cardiopulmonary bypass and selective cerebral perfusion using [O-15]water and PET

Background: Competition between neurotransmitter and radioligands has provided a very useful method to assess synaptic changes in dopamine, but this approach has been slow to extend to other neurotransmitter system. Previously, Fujita and colleagues showed that the high affinity beta2-nicotinic acetylcholine receptor (b2-nAChR) radioligand [I]5-IA85380 (5-IA) may be sensitive to extracellular increases in ACh in baboons; 1 however, such an examination in humans has lagged. Given that acetylcholine is one of the major neurotransmitters in the brain and has been implicated in the psychiatric and medical illnesses, we developed a paradigm to interrogate the ACh system in vivo via use of 5-IA SPECT imaging and physostigmine, a centrally-acting acetylcholinesterase inhibitor. Methods: Six healthy subjects (3 men, 3 women; 31±4.1 yrs) participated in one 5-IA SPECT study. 5-IA was administered as a bolus plus constant infusion (B/I 7.0 h); total injected dose was 390.2±13.2 MBq. After three 30-min baseline scans at 6-8 h post infusion, physostigmine (1-1.5 mg) was administered IV over 60 min, and nine additional 30-min scans were collected during the next 6 h. The outcome measure was BPF (specific volume of distribution), calculated as VT/fp (estimated receptor availability) minus VND/fp (nondisplaceable binding; previously estimated in a smoking to satiety paradigm). Results: We observed a significant reduction in BPF after physostigmine administration (25±15% reduction in cortical regions, 15±11% thalamus (Figure 1), 16±14% in striatum, and 35±34% in cerebellum; p < .05). This effect reflected a combination of a significant decrease in tissue concentration of 5-IA (7-16% region specific, p < .05) and a significant increase in plasma parent concentration (8%, p < .05). Conclusions: These data suggest that physostigmineinduced increases in extracellular ACh might compete with 5-IA for binding to b2-nAChRs in humans, although other mechanisms, such as a direct effect of physostigmine on nicotinic acetylcholine receptors, should be ruled out. Additional validation of this paradigm is warranted, but we suggest that nicotinic imaging could be used to interrogate changes in synaptic ACh.