Ya-Yao Huang

Plasma Aβ but not tau is related to brain PiB retention in early Alzheimer's disease

Recent advances in biomarkers provide the possibility of early or preclinical diagnosis of Alzheimers pathology. Currently, decreased levels of Aβ-42 and increased levels of tau proteins in cerebral spinal fluid are considered reliable biomarkers of Alzheimers disease (AD); however, little evidence exists for the use of amyloid and tau protein levels in the plasma as useful biomarkers. We investigated the potential use of plasma biomarkers to diagnose AD and explored their relationships with brain Aβ deposition in amyloid imaging. We used an immunomagnetic reduction assay to measure the plasma levels of Aβ40, Aβ42, and tau proteins in 20 older control participants and 25 participants who had either mild cognitive impairment due to AD or early AD dementia. All participants received (11)C-labeled Pittsburgh compound B PET scans. The sensitivity of the plasma tau level at the cutoff value of 28.27 pg/mL was 92%, and the specificity was 100%; the sensitivity of the Aβ42/40 ratio at the cutoff value of 0.3693 was 84%, and the specificity was 100%. Regression analyses of the effects of plasma protein levels on brain amyloid retention, as determined by standard uptake value ratios in either side of the frontal, parietal, and temporal lobes and the precuneus, are predicted only by ratios of plasma Aβ42/40 (R(2) 0.326-0.449, all p < 0.001) but not by plasma tau levels. Plasma Aβ in terms of Aβ42/40 might provide an indirect estimation of Aβ deposition in the brain.

An automated synthesis of N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) for imaging serotonin transporters.

N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM, 3) is a potent serotonin transporter (SERT) imaging agent. In order to fulfill the demand of pre-clinical studies, we have developed an automated synthesis unit to synthesize this radioligand. The 4-[(18)F]-ADAM was synthesized using TracerLab FN and FE modules and a modified module control program (TracerLab-Fx). The synthesis sequences were similar to that of the manual synthesis, i.e. nucleophilic fluorination of N,N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1) with K[(18)F]/K(2.2.2) followed by reduction with NaBH(4)/Cu(OAc)(2) and purifications with high-performance liquid chromatography (HPLC) and solid phase extraction. The radiochemical yield of 3 was 1.5+/-0.3% (n=13, EOS). The synthesis time was 120 min and the specific activity was 1.75+/-0.77 Ci/micromol (n=13, EOS). The 4-[(18)F]-ADAM synthesized by this module was stable over 4h at room temperature and is suitable for imaging SERT in humans.

An improved synthesis of 4-[18F]-ADAM, a potent serotonin transporter imaging agent.

An improved synthesis of N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM, 2) as a potent serotonin transporter (SERT) imaging agent is described. Molecular orbital (MO) calculation predicts that N,N-dimethyl-2-(2-nitro-4-trimethylammoniumtrifluoromethanesulfonylphenylthio)benzamide (8) is probably a better precursor than N,N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1) for preparing 2. Radioligand 2 was synthesized by the reaction of either precursor 1 or precursor 8 with K[(18)F]/K(2.2.2) at 120 degrees C followed by reduction with BH(3) at 80 degrees C. The radiochemical yield (EOB) of 2 synthesized from precursor 1 and 8 was 5.7+/-2.4% (n=6) and 14.8+/-4.0% (n=5), respectively, in a synthesis time of 120 min from EOB. The specific activity of 2 was 3 Ci/micromol or 111 GBq/micromol (EOB). Thus, this new synthetic method has significantly improved the radiochemical yield of 4-[(18)F]-ADAM and makes this radioligand more accessible to PET Centers without a cyclotron.

Synthesis and comparison of 4-[18F]F-ADAM, 2-[18F]F-ADAM, N-Desmethyl-4-[18F]F-ADAM and [18F]F-AFM as serotonin transporter imaging agents

4-[(18)F]F-ADAM (1a), 2-[(18)F]F-ADAM (2a), N-Desmethyl-4-[(18)F]F-ADAM (3a) and [(18)F]F-AFM (4a ) were synthesized in 1.7, 3.9, 2.9 and 0.6% yield (EOS), respectively, in a synthesis time of ~120 min from EOB. PET studies in rats showed that the maximum specific uptake ratios of 1a, 2a, 3a and 4a in midbrain were 3.86, 0.73, 0.35 and 2.23, respectively. Thus, in terms of radiochemical yield, specific binding and in vivo stability, 4-[(18)F]F-ADAM may be the most appropriate SERT imaging agent for human studies.

Performing Repeated Quantitative Small Animal PET Studies with Arterial Input Functions is Routinely-Feasible in Rats

Performing quantitative small-animal PET with an arterial input function has been considered technically challenging. Here, we introduce a catheterization procedure that keeps a rat physiologically stable for 1.5 mo. We demonstrated the feasibility of quantitative small-animal 18F-FDG PET in rats by performing it repeatedly to monitor the time course of variations in the cerebral metabolic rate of glucose (CMRglc). Methods: Aseptic surgery was performed on 2 rats. Each rat underwent catheterization of the right femoral artery and left femoral vein. The catheters were sealed with microinjection ports and then implanted subcutaneously. Over the next 3 wk, each rat underwent 18F-FDG quantitative small-animal PET 6 times. The CMRglc of each brain region was calculated using a 3-compartment model and an operational equation that included a k*4. Results: On 6 mornings, we completed 12 18F-FDG quantitative small-animal PET studies on 2 rats. The rats grew steadily before and after the 6 quantitative small-animal PET studies. The CMRglc of the conscious brain (e.g., right parietal region, 99.6 ± 10.2 μmol/100 g/min; n = 6) was comparable to that for 14C-deoxyglucose autoradiographic methods. Conclusion: Maintaining good blood patency in catheterized rats is not difficult. Longitudinal quantitative small-animal PET imaging with an arterial input function can be performed routinely.

The Relation Between Brain Amyloid Deposition, Cortical Atrophy, and Plasma Biomarkers in Amnesic Mild Cognitive Impairment and Alzheimer’s Disease

Background: Neuritic plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimers disease (AD), while the role of brain amyloid deposition in the clinical manifestation or brain atrophy remains unresolved. We aimed to explore the relation between brain amyloid deposition, cortical thickness, and plasma biomarkers. Methods: We used 11C-Pittsburgh compound B-positron emission tomography to assay brain amyloid deposition, magnetic resonance imaging to estimate cortical thickness, and an immunomagnetic reduction assay to measure plasma biomarkers. We recruited 39 controls, 25 subjects with amnesic mild cognitive impairment (aMCI), and 16 subjects with AD. PiB positivity (PiB+) was defined by the upper limit of the 95% confidence interval of the mean cortical SUVR from six predefined regions (1.0511 in this study). Results: All plasma biomarkers showed significant between-group differences. The plasma Aβ40 level was positively correlated with the mean cortical thickness of both the PiB+ and PiB- subjects. The plasma Aβ40 level of the subjects who were PiB+ was negatively correlated with brain amyloid deposition. In addition, the plasma tau level was negatively correlated with cortical thickness in both the PiB+ and PiB- subjects. Moreover, cortical thickness was negatively correlated with brain amyloid deposition in the PiB+ subjects. In addition, the cut-off point of plasma tau for differentiating between controls and AD was higher in the PiB- group than in the PiB+ group (37.5 versus 25.6 pg/ml, respectively). Lastly, ApoE4 increased the PiB+ rate in the aMCI and control groups. Conclusion: The contributions of brain amyloid deposition to cortical atrophy are spatially distinct. Plasma Aβ40 might be a protective indicator of less brain amyloid deposition and cortical atrophy. It takes more tau pathology to reach the same level of cognitive decline in subjects without brain amyloid deposition, and ApoE4 plays an early role in amyloid pathogenesis.

High yield one-pot production of [18F]FCH via a modified TRACERlab FxFN module

INTRODUCTION [18F]Fluoromethylcholine ([18F]FCH) is a potent tumors imaging agent. In order to fulfill the demand of pre-clinical and clinical studies, we have developed an automated high yield one-pot synthesis of this potent tumors imaging agent. METHODS [18F]FCH was synthesized using a modified TRACERlab FxFN module. Briefly, dibromomethane (10% in CH3CN) was fluorinated with K[18F]/K 2.2.2 in a glassy carbon reaction vessel at 120°C for about 5min to generate [18F]fluorobromomethane ([18F]FBM). The resulting [18F]FBM was then bubbling (He, 700mL/min) through four Sep-Pak® Silica Plus Long cartridges to react with dimethylaminoethanol (10% DMAE in 0.3mL DMSO) which was pre-loaded on Sep-Pak® C18 Plus Short cartridge. The [18F]FCH was purified by solid-phase extraction (SPE) using one Sep-Pak® C18 Plus Short and one Sep-Pak® CM Plus Short in series. The quality of [18F]FCH synthesized by this method was verified by HPLC and TLC as compared to authentic sample. RESULTS Using this improved one-pot method, the RCY of [18F]FCH was 18.8 ± 2.1% (EOB, n = 27) in a synthesis time of 49 ± 5min from EOB. The radiochemical purity of [18F]FCH was greater than 90% and the residual DMAE concentration in the final product was less than 10ppm. CONCLUSIONS This optimized method could fulfill the demand of [18F]FCH for both pre-clinical and clinical studies, especially for nearby study sites without a cyclotron.

A Novel Potential Positron Emission Tomography Imaging Agent for Vesicular Monoamine Transporter Type 2.

In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomography (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better average radiochemical yield of 35.3 ± 3.6% (decay-corrected to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our experiment is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains.

Erratum to: Toxicity and radiation dosimetry studies of the serotonin transporter radioligand [18F]AFM in rats and monkeys

Erratum Unfortunately, the original version of this article was published with incorrect details for one authors name and address. Cheng-Yi Cheng’s name, which had been incorrectly spelled as Chen-Yi Cheng, has been corrected. The author’s correct address is as follows: PET Center, Department of Nuclear Medicine, TriService General Hospital, National Defense Medical Center, 325 Sec. 2, Cheng-Kung Road, Taipei 114, Taiwan.

A Comparison Study between LAL Endotoxin Test Methodologies of PET Radiotracers: Endosafe®-PTS^(TM) System and Kinetic Chromogenic Analysis

Background: The pyrogen test represents an important parameter for the quality control (QC) of PET tracers. However, the standard test proposed by the U.S. Pharmacopeia using limulus amebocyte lysates takes too long (about 1 h) for short-lived PET tracers. Endosafe® Portable Test System (PTS) has been approved by FDA and was claimed that it takes approximately 15 min to complete test procedure. The aim of this study was to evaluate PTS performance for PET tracers and head-to-head comparison with kinetic chromogenic analysis (KCA) that routinely used in NTUH PET center. Methods: With PTS and the conventional assay method, Lonza KCA assay systems, both experiments were performed on 3 consecutive batches of on-site produced F-18 FDG, C-11 PiB and N-13 NH3 by 6 different executors. All samples were tested with PTS method using 0.05~5.0EU/mL sensitivity cartridges. Additionally, for purpose to verify the accuracy of results from these two endotoxin test methods and the reliability regarding operative procedures among 6 QC staff, fabricated endotoxinpositive samples containing a fixed concentration of USP validated reference standard endotoxin (RSE) were also prepared and tested for blind testing. Results: The results of endotoxin detection among these two methods involving KCA and PTS were similar in most cases, although PTS exhibited significantly shorter time in testing (about 16~17 minutes required). However, results of blind test indicate that the control standard endotoxin used in KCA method has significant impact on the test results, such as inappropriate storage conditions of control standard endotoxin, and the KCA measurement is the most time-consuming method among these three methods. Conclusions: TPTS provided as reliable results as KCA method for endotoxin test and even more rapidly, therefore, is most suitable for short-lived PET radiotracers. Thus, the use of PTS will simplify the routine QC procedures of short-lived PET radiopharmaceuticals and prevent undetectable errors. Also, it will be of benefit to clinical application and future development of PET radiotracers.