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Preliminary PET study of F-FC119S in normal and Alzheimer’s disease models. Se Jong Oh, Min Hwan Kim, Sang Jin Han, Kyung Jun Kang, In Ok Ko, YoungSoo Kim, Ji Ae Park, Jae Yong Choi, Kyo Chul Lee, Dae Yoon Chi, Yong Jin Lee, and Kyeong Min Kim Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00351 • Publication Date (Web): 24 Jul 2017 Downloaded from http://pubs.acs.org on July 24, 2017

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Molecular Pharmaceutics

Preliminary PET study of 18F-FC119S in normal and Alzheimer’s disease models Se Jong Oh1,2‡, Min Hwan Kim1‡, Sang Jin Han1, Kyung Jun Kang1, In Ok Ko1, YoungSoo Kim3, Ji-Ae Park1, Jae Yong Choi1, Kyo Chul Lee1, Dae Yoon Chi4, Yong Jin Lee1,*, Kyeong Min Kim2,5,* 1

Division of RI-Convergence Research, Korea Institute Radiological and Medical Sciences,

Seoul, Korea 2

Radiological & Medico-Oncological Sciences, University of Science and Technology, Daejeon,

Korea 3

Department of Pharmacy and Integrated Science and Engineering Division, Yonsei University,

Incheon, Korea 4

Research Institute of Labeling, FutureChem Co., Ltd, Seoul 04782, Republic of Korea

5

Division of Medical Radiation Equipment, Korea Institute Radiological and Medical Sciences,

Seoul, Korea

1 Environment ACS Paragon Plus


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ABSTRACT

To evaluate the efficacy of

18

F-FC119S as a positron emission tomography (PET)

radiopharmaceutical for the imaging of Alzheimer's disease (AD), we studied the drug absorption characteristics and distribution of evaluated the specificity of

18

18

F-FC119S in normal mice. In addition, we

F-FC119S for β-amyloid (Aβ) in the AD group of an APP/PS1

mouse model and compared it with that in the wild-type (WT) group. The behavior of

18

F-

FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F-FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of

18

F-FC119S showed highly specific

binding of the molecule to Aβ in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18

F-FC119S would be a candidate PET imaging agent for targeting Aβ plaque.

KEYWORDS: Alzheimer's disease (AD), 18F-FC119S, β-amyloid (Aβ)


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INTRODUCTION Alzheimer's disease (AD), the most common cause of dementia, can engender problems, including memory loss and a decline in intellectual abilities. The number of people suffering from AD worldwide consistently increases every year and is expected to reach approximately 106.8 million by 2050.1 Although the prevalence of AD continues to increase, adequate diagnosis and treatment of this disorder are lacking.2 Therefore, the evaluation of AD based on molecular imaging has become an area of great interest in the field of neuroscience.3,4 The cardinal pathological hallmarks of AD include abnormally hyperphosphorylated tau and βamyloid (Aβ) deposition in the brain.5 Early diagnosis is especially important for lowering the prevalence of AD because clinical symptoms appear after the disease has progressed considerably.6 Positron emission tomography (PET) is considered as a promising tool for studying the central nervous system because it provides both biochemical and physiological information from a living system. Glucose PET, which uses

18

F-FDG (fluorodeoxyglucose), can measure the

cerebral metabolic rate of glucose as a representative of neural activity. However, the uptake of 18

F-FDG is affected by inflammation and ischemic condition.7 In the past few decades, Aβ has

been recognized as an important diagnostic biomarker for AD; as a result, many Aβ PET tracers have been developed.8 11C-labeled Pittsburgh compound B (11C-PIB) has frequently been used in the clinical studies. However, 11C has a short half-life of only 20 min and thus cannot be used at a site that is located far from a synthesis facility.9 Consequently, 18F-labeled PET tracers (T1/2 = 109 min) have been developed. Currently, three radiotracers have been approved by the US Food and Drug Administration (FDA) for human use: Company),10

18

18

F-florbetapir (AMYViDTM, Eli Lilly and

F-flutemetamol (VizamylTM, GE Healthcare)11 and


18

F-florbetaben (NeuraCeqTM,


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Piramal Imaging).9,10,12 Studies of

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F-NAV4694 and

18

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F-FIBT in human subjects are also

ongoing.13,14 In our previous study, we found that 18F-labeled 2-[2-(N-monomethyl)aminopyridine-6-yl]-6[(S)-3-fluoro-2-hydroxypropoxy]benzothazole (18F-FC119S) has a high binding affinity for the Aβ1-42 protein aggregate (0.16 nM) and AD brain homogenate (13-15 nM).

18

F-FC119S was

distinctly excreted from the frontal cortex of healthy rhesus monkeys. Moreover, in autoradiography on human brain tissues, the radiotracer showed high specificity for Aβ.15 However, the biological efficacy of

18

F-FC119S in an actual AD model has not yet been

reported. Thus, the purpose of the present study is to examine the pharmacokinetic properties of 18

F-FC119S in an AD mouse model.

MATERIALS AND METHODS Animals The care, maintenance, and treatment of animals in these studies followed protocols approved by the Institutional Animal Care and Use Committee of the Korea Institute of Radiological & Medical Sciences (KIRAMS), and the experiments involving animals were conducted according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. The living chambers for animals were automatically controlled with a 12 h light/dark cycle and at a temperature of 22 ± 3 °C and relative humidity of 55 ± 20%. A sterilized rodent diet and purified tap water were supplied ad libitum. To acclimate the animals, they were raised under the conditions described above for a week prior to their use in experiments. Three groups of mice were used for these studies: Group I: Normal male C57BL/6 mice aged 8 weeks and used for the biodistribution study and PET imaging. Group II: Double APP/PS1 transgenic mice


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(strain name: B6C3-Tg (APPswe, PSEN1De9)85Dbo/J) aged 20 months and used for PET brain imaging as a model that mimics the early onset of AD. This mouse model is known to develop the first plaques in the cortex and hippocampus at 4 months of age.16 Group III: Wild-type (WT) (B6C3F1) aged 20 months and used as a control for Group II.

Radiosynthesis of 18F-FC119S 18

F-FC119S was prepared according to a previously described procedure.17 The radiochemical

purity was 97%, and the specific activity was > 44GBq/µmol.

Biodistribution studies Male C57BL/6 mice (Group I) were anesthetized with 2.5% isoflurane in oxygen. Next, 3.0 ~ 3.7 MBq of

18

F-FC119S in 100 µL of saline was injected intravenously (i.v.) via the tail vein.

Mice (n = 6 each) were sacrificed, and tissues of interest (i.e., blood, muscle, heart, lung, liver, spleen, stomach, intestine, kidney, striatum, cerebrum and the rest of the brain) were collected and weighed. The radioactivities of these samples were measured using a γ-counter (1480 Wizard 3” Automatic Gamma Counter; PerkinElmer, Inc.). Each tissue uptake was expressed as a percentage of injected dose per gram (% ID/g).

PET imaging To evaluate biodistribution, PET/CT imaging of

18

F-FC119S distribution was performed on

normal C57BL/6 mice (Group I, n = 5), and to evaluate the Aβ targeting ability of 18F-FC119S, PET/CT imaging was performed on double APP/PS1 transgenic mice (Group II, n = 5) and their WT counterparts (Group III, n = 4), respectively.



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Whole-body PET images of the mice were obtained using a small animal PET/CT scanner (nanoScan®, Mediso Medical Imaging Systems, Budapest, Hungary). Mice were anesthetized with 2.5% isoflurane in oxygen, and 8.3 ~ 9.7 MBq of

18

F-FC119S in 200 µL of saline was

injected i.v. via the tail vein with a syringe pump (KDS 210, KD Scientific, Holliston, MA, USA) over 1 min. Dynamic PET scanning was performed for 130 min with 28 frames (14 × 30 s, 3 × 60 s, 4 × 300 s, 3 × 600 s, and 3 × 1200 s) and 60 min with 24 frames (14 × 30 s, 3 × 60 s, 4 × 300 s, and 3 × 600 s) for Group I and Groups II and III, respectively. The image scans were acquired with an energy window of 400 ~ 600 keV. All images were reconstructed using the 3dimensional ordered subset expectation maximization (3D-OSEM) algorithm with 4 iterations and 6 subsets. For attenuation correction and anatomical reference, micro-CT imaging was conducted immediately after PET using 50 kVp of X-ray voltage with 0.16 mAs.

MRI imaging To define the anatomical volumes of interest (VOIs), MR scans were obtained on a 31 cm horizontal-bore Agilent 9.4 T scanner (Agilent Technologies, Santa Clara, CA, USA) using a 2channel array mouse head surface coil (Rapid Biomedical GmbH, Rimpar, Germany). The image parameters for the TSE 3D T2 weighted image were as follows: repetition time (TR) = 2500 ms; echo time (TE) = 7.45 ms; FOV = 20 mm × 20 mm × 10 mm; matrix size = 128 × 128 × 64; voxel size = 0.156 µm × 0.156 µm × 0.156 µm; ETL = 64; and scan time = 2 h 50 m 50 s. During imaging, the respiratory rate of the mice was monitored using an MR-compatible physiological monitoring and gating system (SA Instruments Inc., Stony Brook, NY, USA).

Image analysis of Group I


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For image analysis, dynamic PET images were co-registered with the CT image, and under guidance of the CT image, VOIs were manually drawn over the heart, lung, liver, kidney, bone, blood, gallbladder, cerebrum and cerebellum (Group I). The uptake values were expressed as % ID/g, which was calculated as follows: VOI activity divided by injected dose multiplied by 100%. This analysis was performed using InterView Fusion software (Mediso Medical Imaging Systems).

Brain PET image analysis of Groups II and III To compare the regional

18

F-FC119S uptake in Groups II (AD group) and III (WT group),

three-dimensional VOIs were drawn. Briefly, dynamic

18

F-FC119S PET images were motion-

corrected and co-registered to the corresponding MRI for each mouse. The MR images were then spatially normalized to the M. Mirrione T2-weighted mouse brain MRI template found in PMOD software (version 3.4, PMOD Group, Graubunden, Switzerland), and the normalization factor values were applied to the corresponding dynamic PET images.10 Three VOIs of the cerebral cortex (CTX), hippocampus (HIP), and cerebellum (CB) were defined on the MRI template (Figure 1). This process was conducted using PMOD Fusion Tool software. Finally, time activity curves (TACs) of the three regions were obtained. The obtained uptake value, which is represented as the standardized uptake value (SUV), was determined for each region. The SUV values obtained for each region of activity were multiplied by the mouse weight divided by the injected dose.18 The distribution volume ratios (DVRs) from 10 to 60 min were estimated using Logan graphical analysis to compare the level of Aβ retention between Groups II and III.19 The CB was used as a reference region. In addition, the cortical and hippocampal standardized uptake value



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ratios (SUVRs) relative to that of the cerebellum (CTX/CB and HIP/CB retention ratios)11 were calculated for the 30-60 min phase for the static image because the target-to-reference ratios showed a plateau during this period. Based on the above results, the correlation between the DVR and SUVR was investigated. All image analyses were carried out using PMOD software.

Statistical analysis The quantitative results are expressed as the mean ± SD. All statistical results were analyzed with GraphPad Prism software (GraphPad Software, Inc., La Jolla, CA, USA). Student’s t-test was used to determine statistical significance at a 95% confidence level, and a P < 0.05 was considered significantly different.

RESULTS Biodistribution studies The biodistribution profiles for

18

F-FC119S in the normal healthy mice (Group I) are

summarized in Figure S1 and Table S1. In general, rapid distribution and clearance of

18

F-

FC119S was observed in the brain. The highest uptake was found 1 min post-injection (p.i.) for the cerebrum, striatum and the rest of the brain (12.90 ± 0.95, 16.48 ± 2.11, and 21.50 ± 7.78% ID/g, respectively), and these values then rapidly decreased due to passive diffusion into the blood stream. Uptake was high in the kidneys at 1 min p.i. (52.37 ± 4.71% ID/g) but significantly decreased at 5 min p.i. (26.18 ± 6.27% ID/g). High accumulation of 18F-FC119S was also observed in the liver and intestine, which are metabolism- and excretion-related organs. In the case of liver uptake, the maximum value was at 1 min p.i. (48.89 ± 13.07% ID/g), and this value further


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decreased at 10 min and 60 min (34.63 ± 7.02 and 3.9 ± 1.41% ID/g, respectively). For

18

F-

FC119S, the highest uptake in the intestine was at 60 min p.i. (74.28 ± 6.64% ID/g), an increase from the uptake at 1 min p.i. (14.32 ± 2.89% ID/g). The pharmacokinetic (PK) properties of

18

F-FC119S were investigated based on in vivo

biodistribution results. As shown in Table S2, in the blood, heart, spleen, kidneys and brain, 18FFC119S reached a maximum concentration at 1 min p.i. The Tmax values of the lung and liver were between 2.5 and 3.4 min, while the Tmax values of the stomach and intestine were 21 and 72 min, respectively.

PET imaging study of normal mice (Group I) To evaluate the efficacy of

18

F-FC119S, dynamic PET scans were performed on normal mice,

and the PK parameters were calculated (Tmax, Cmax, area under the curve (AUC), and T1/2). The data are shown in Table S3, and the high-contrast PET images and TACs of the brain are shown in Figure 2. The PET images revealed that during the initial phase, the radioactivity mainly accumulated in the brain and liver (Figure 2A), and it remained in the gallbladder, intestine and bladder in the late phase (Figure 2B). This result demonstrated that

18

F-FC119S effectively

passes through the brain and was clearly washed out from the normal brain regions. The brain uptake increased substantially during the initial phase (0 ~ 4 min), and then the drug was rapidly excreted from the brain during the late phase (110 ~ 130 min). The brain TAC is shown in Figure 2C (those of the other organs are shown in Figure S2). The T1/2 value was 8.7 min (Table S3), and the ratio of brain2min/brain60min was 8.03 (Table S4). In the skull, the radioactivity showed a rapid washout pattern (Figure 2D), indicating that 18F-FC119S has metabolic stability against in vivo defluorination.



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PET imaging study of AD and WT mice (Groups II and III) Brain uptake of 18F-FC119S The ability of

18

F-FC119S to bind to Aβ plaques in vivo was assessed by acquiring 60 min

dynamic PET scans of the APP/PS1 (AD group) and B6C3F1 mice (WT group) (Figure 3). By visual inspection, the PET images indicated that both groups showed high 18F-FC119S retention during the initial phase (0 ~ 10 min), mainly due to the effects of cerebral blood flow. Similar to 11

C-PIB and

18

F-florbetaben,

18

F-FC119S showed non-specific uptake in the nasal and eye

cavities for both groups, and this uptake was even observed in the late phase.20, 21 Compared to the WT group, the AD group showed higher

18

F-FC119S retention in the brain

region during the middle and late phases (10 ~ 30 and 30 ~ 60 min, respectively), indicating the specific binding of 18F-FC119S to Aβ.

Comparison of regional time activity curves To evaluate the difference of regional uptake patterns between the AD and WT groups, we analyzed the TACs in target regions (CTX and HIP) known to contain high concentrations of Aβ.16 Both groups showed rapid entry of

18

F-FC119S into the target regions. In the AD group

(Figure 4A) between 10 and 60 min, the target regions showed increased

18

F-FC119S uptakes

compared with those in the WT group (Figure 4B). In terms of the AUC between 10 and 60 min, the AD group (CTX: 7.62 ± 2.02, HIP: 6.66 ± 1.81) showed higher values than those the WT group (CTX: 5.48 ± 0.59, HIP: 5.10 ± 0.40). The TAC patterns of the CB were similar between the two groups, except for a minimal change detected during the early phase (Figure 4C), and the AUC values between 10 and 60 min were almost the same (AD: 5.83 ± 0.84, WT: 5.85 ± 0.55).


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No significant differences in the AUC values were observed in the three regions between the AD and WT groups.

Quantitative analysis of Aβ deposition with 18F-FC119S In addition to qualitative evaluation of the PET images, we estimated binding values quantitatively based on the DVR and SUVR. The mean DVR values are given in Figure 5A. The results showed that the AD and WT groups showed significant differences in the CTX and HIP regions. The cortical DVR values of the AD mice were higher than those of the WT mice (AD: 1.12 ± 0.06, WT: 0.91 ± 0.07, P < 0.05). The hippocampal DVRs of the AD group were also higher than those of the WT group (AD: 1.03 ± 0.12, WT: 0.87 ± 0.04, P < 0.05). The mean SUVR values from the 30 ~ 60 min static image are presented in Figure 5B. In the AD group, the cortical SUVR30-60 was higher than that of the WT group (AD: 1.30 ± 0.11, WT: 1.01 ± 0.08, P < 0.05). In the case of hippocampal, the AD group also displayed a higher SUVR30-60 than the WT group (AD: 1.12 ± 0.19, WT: 0.86 ± 0.07, P < 0.05). These results were consistent with the previous DVR results. The quantitative values of DVR and SUVR provided the clear differentiation between the AD and WT groups, in contrast to the TAC results.

Correlation between DVR and SUVR30-60 The kinetic modeling technique (i.e., Logan graphical analysis), which is based on lengthy dynamic PET acquisition (1 ~ 2 h), requires a large amount of data and sophisticated analysis. By contrast, the SUVR method utilizes relatively short static acquisition and simple analysis (20



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~ 30 min); thus, the burden on the patient is reduced. Therefore, SUVR approaches are desirable for clinical study. The possibility of applying a time window for static PET (30 ~ 60 min) was evaluated by investigating the correlation between DVR and SUVR30-60 (Figure 5C). The SUVR value was generally overestimated relative to the DVR value but showed a highly correlated plot with a regression slope of 1.50 (r2 = 0.88). This result indicates that using a window of 30 ~ 60 min would be useful in additional static 18F-FC119S PET experiments in rodents.

DISCUSSION In the present study, we examined the pharmacokinetics and in vivo efficacy of 18F-FC119S in rodents.

18

F-FC119S displayed a rapid uptake and washout pattern in normal mice and

demonstrated high specificity for Aβ burden. The binding values in the AD group were higher than those in the WT group. These results demonstrate that

18

F-FC119S possesses stable PK

characteristics in the analyzed AD mouse model, suggesting that it may be suitable as an Aβ imaging agent. 18

F-FC119S has comparable kinetic properties to previously developed Aβ imaging

radiopharmaceuticals. In general, clinically effective PET radioligands enter the brain of mice within a few minutes after i.v. injection, reaching a peak value of >4% ID/g of brain tissue.22 The peak value of 18F-FC119S in the brain was observed to be approximately 5.4% ID/g (Figure 2C), a value comparable to the values observed for

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F-florbetapir (2 min, 6.8% ID/g)23,

18

F-

flutemetamol (2 min, 5 ~ 6% ID/g)24 and 18F-florbetaben (2 min, 4.77% ID/g)2 in normal mouse brains. Our findings indicate that

18

F-FC119S has a high brain penetration and rapid clearance

rate from the non-specific regions of the brain.


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Lipophilicity is also a useful indicator of the level of penetration of molecules into the brain, and the LogP value is the most commonly used index of lipophilicity.25 Literature precedents have suggested that brain PET radiotracers have moderate log P values (0.9 and 2.5).26

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F-

FC119S has experimental LogP of 2.12, which meets the acceptance criteria. According to previous studies on the use of

11

C-PIB and

18

F-florbetaben, there was no

significant difference in Aβ aggregation between APP/PS1 and WT mice.19,27 By contrast,

18

F-

FC119S showed a significantly higher binding value in the APP/PS1 mice than in their WT counterparts. These results are primarily attributable to the difference in specific activity, i.e., the ratio of radioactivity to cold mass. For radiotracers with high specific activity, the majority of the radioactivity binds to the molecular target without interference from the non-radioactive component; therefore, brain PET radiotracers must have a high specific activity. In our facility, we confirmed that

18

F-FC119S has a slightly higher specific activity than

GBq/µmol, respectively).17 Another hypothesis is that

18

11

C-PIB (44 and 35

F-FC119S has a high binding affinity.

18

F-FC119S has a binding affinity (Ki) of 0.16 nM, which is higher than those of

18

F-florbetaben (Ki = 0.44 and 6.7 nM, respectively).15,28 Recently developed radiotracers such

as

18

F-FIBT and

18

11

C-PIB and

F-NAV4694 also have lower binding affinities (Ki = 2.1 and 18.5 nM,

respectively) than 18F-FC119S.14,29 Further investigation is required to address this issue. 18

of

F-FC119S showed rapid clearance from the brain, preventing non-specific binding. The T1/2

18

F-FC119S in the normal mouse brain is 8.7 min (Table S3), which satisfies the

recommendation that the T1/2 of an ideal Aβ imaging drug should be less than 30 min.21 Furthermore, the brain2

min/brain60 min

ratio has been used as an important index to evaluate

clearance, and the brain2 min/brain60 min ratio of 18F-FC119S (equal to 8.03, Table S4) is twice as



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high as that of 18F-florbetapir (brain2 min/brain60 min ratio = 3.80).26 These results indicate that 18FFC119S has the properties necessary to minimize non-specific binding. Current AD mouse models have limitations, including incompatible results. Although 11C-PIB can detect the degree of amyloidosis in humans, the radiopharmaceutical failed to differentiate AD mice from WT mice. Toyama et al. suspected that 11C-PIB did not effectively bind to Aβ in the transgenic mice.30 When presenilin-1 (PS1) was concurrently administered to the amyloid precursor protein transgenic (APP) mice, 11C-PIB showed significant results compared with the WT mice.20 However, Klunk et al. reported no significant differences in binding in APP/PS1 mice using the same radiotracer.31 The exact reason for these results is unknown, and additional validation of the AD mouse models is required.

CONCLUSION In summary, the pharmacokinetic data from the normal mice showed that the initial inflow of 18

F-FC119S to the brain was high and then that 18F-FC119S was washed out rapidly. In addition,

18

F-FC119S showed high specificity for the target regions, and confirmation of the increase in

Aβ in the AD group was possible. Therefore, 18F-FC119S may be a useful preclinical candidate PET radiotracer.


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FIGURE LEGENDS Figure 1. Definitions of three VOIs, consisting of the cortex (green), hippocampus (blue), and cerebellum (yellow), in the co-registered MRI-PET image. The PET and MR images were spatially normalized to the T2-weighted mouse brain MR template. Figure 2. Whole-body

18

F-FC119S PET images in the coronal and sagittal planes of normal

mice during the initial phase (0 ~ 4 min, A) and late phase (110 ~ 130 min, B). The TACs for 18

F-FC119S in the whole brain for the entire 130 min PET scan (C). The

18

F-FC119S in the skull (D). Data represent the mean ± SD.

Figure 3.

18

18

F-FC119S TACs of

F-FC119S PET images co-registered to in vivo 9.4T MR images of the WT group

(A) and AD group (B). PET images in each row represent summed over 0 ~10, 10 ~ 30 and 30 ~ 60 min p.i. The columns from left to right show the coronal, sagittal, and axial views. Figure 4. Regional dynamic PET TACs for the CTX and HIP regions of the WT (A) and AD groups (B). The activity from 10 to 60 min for each result was magnified on the upper right. The TACs of the CB region for both groups (C). Data were expressed as the mean (n = 4 for WT; and n = 5 for AD). Figure 5. (A) The DVR values and (B) SUVR values from static images during the interval of 30 ~ 60 min after 18F-FC119S injection. (C) Scatter plot of the relationship between the SUVR during the time period of 30 ~ 60 min in the static frame and the DVR. Dotted line represents the line of origin.



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Figure 4.


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Figure 5.


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ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: Biodistribution results for 18F-FC119S in normal mice, the time activity curves for multiple mouse organs, and pharmacokinetic parameters based on PET images of normal mice.

AUTHOR INFORMATION Corresponding Author *

To whom correspondence should be addressed. For Yong Jin Lee: Phone: (+)82-2-970-1364;

Fax: +82-2-970-1341; E-mail: [email protected]. For Kyeong Min Kim: Phone: (+)82-2-9701387; E-mail: [email protected]. Author Contributions ‡

These authors contributed equally.

Notes The authors declare that they have no conflicts of interest.

ACKNOWLEDGMENTS FutureChem (Korea) is acknowledged for the synthesis of

18

F-FC119S. This research was

supported by a grant of the Korea Institute of Radiological and Medical Sciences (KIRAMS) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea. (No.



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1711045578;

1711045556;

1711045577;

1711045576/50532-2017,

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1711045539;

171104541/50461-2017).

ABBREVIATIONS PET, positron emission tomography; AD, Alzheimer's disease; WT, wild-type; Aβ, β-amyloid; OSEM 3D, 3-dimensional ordered subset expectation maximization; PK, pharmacokinetic; AUC, area under the curve; CTX, cortex; HIP, hippocampus; CB, cerebellum; TACs, time activity curves; SUV, standardized uptake value; DVR, distribution volume ratio; SUVR, standardized uptake value ratio.


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