Current Role at Stanford
I joined in Cyclotron and radiochemstry facility in 2014. I focus on routine radiopharmaceutical production, including 18F tracers (18F-Flumazenil, 18F-FTC-146, 18F-FLT, 18F Arag, 18F-FSPG etc.); 11C tracers (11C UCB-J, 11C-raclopride, 11C-PIB, 11C-methionine, 11C DPA-713 etc.); 15O-H2O and 68Ga-DOTATATE radiochemistry for clinical use and supporting various of pre-clinical studies.
Development, optimization of Radiopharmaceuticals,
Radiochemistry Research Assistant, Cyclotron and Radiochemistry Facility, Department of Radiology, School of Medicine, Stanford (9/27/2014 - Present)
1201 Welch Road
Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder.
The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.
View details for DOI 10.1038/s41380-020-0756-y
View details for PubMedID 32376999
Carbon-11 labeled BLZ945 as PET tracer for Colony Stimulating Factor 1 Receptor imaging in the brain
WILEY. 2019: S487–S488
View details for Web of Science ID 000468965200407
- Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [O-15]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database STROKE 2019; 50 (2): 373–80
Simultaneous phase-contrast MRI and PET for noninvasive quantification of cerebral blood flow and reactivity in healthy subjects and patients with cerebrovascular disease.
Journal of magnetic resonance imaging : JMRI
H215 O-positron emission tomography (PET) is considered the reference standard for absolute cerebral blood flow (CBF). However, this technique requires an arterial input function measured through continuous sampling of arterial blood, which is invasive and has limitations with tracer delay and dispersion.To demonstrate a new noninvasive method to quantify absolute CBF with a PET/MRI hybrid scanner. This blood-free approach, called PC-PET, takes the spatial CBF distribution from a static H215 O-PET scan, and scales it to the whole-brain average CBF value measured by simultaneous phase-contrast MRI.Observational.Twelve healthy controls (HC) and 13 patients with Moyamoya disease (MM) as a model of chronic ischemic disease.3T/2D cardiac-gated phase-contrast MRI and H215 O-PET.PC-PET CBF values from whole brain (WB), gray matter (GM), and white matter (WM) in HCs were compared with literature values since 2000. CBF and cerebrovascular reactivity (CVR), which is defined as the percent CBF change between baseline and post-acetazolamide (vasodilator) scans, were measured by PC-PET in MM patients and HCs within cortical regions corresponding to major vascular territories. Statistical Tests: Linear, mixed effects models were created to compare CBF and CVR, respectively, between patients and controls, and between different degrees of stenosis.The mean CBF values in WB, GM, and WM in HC were 42 ± 7 ml/100 g/min, 50 ± 7 ml/100 g/min, and 23 ± 3 ml/100 g/min, respectively, which agree well with literature values. Compared with normal regions (57 ± 23%), patients showed significantly decreased CVR in areas with mild/moderate stenosis (47 ± 17%, P = 0.011) and in severe/occluded areas (40 ± 16%, P = 0.016). Data Conclusion: PC-PET identifies differences in cerebrovascular reactivity between healthy controls and cerebrovascular patients. PC-PET is suitable for CBF measurement when arterial blood sampling is not accessible, and warrants comparison to fully quantitative H215 O-PET in future studies.3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019.
View details for PubMedID 31044459
Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent 11C-raclopride positron emission tomography and functional magnetic resonance imaging investigation.
2018; 8 (1): 264
Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.
View details for PubMedID 30504860
COMPARISON OF THREE METABOLIC PET RADIOTRACERS IN GLIOBLASTOMA: CELL CULTURE AND ANIMAL STUDIES
OXFORD UNIV PRESS INC. 2018: 34
View details for Web of Science ID 000460646300129
F-FTC-146 in humans.
Journal of nuclear medicine
The purpose of this study is to assess safety, biodistribution and radiation dosimetry in humans for the highly selective sigma-1 receptor (S1R) positron emission tomography (PET) agent (18)F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ((18)F-FTC-146). Methods: Ten healthy volunteers (HV; five female, five male; age: 34.3 ± 6.5 years) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/magnetic resonance imaging (PET/MRI) examinations were acquired for up to three hours after injection (357.2 ± 48.8 MBq). Blood samples were collected and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions-of-interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry was estimated using PMOD 3.7 and Organ Linear Internal Dose Assessment (OLINDA). Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to (18)F-FTC-146 were reported. High accumulation of (18)F-FTC-146 was observed in S1R dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose (ED) of (18)F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range: 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade (18)F-FTC-146 were successful. Injection of (18)F-FTC-146 is safe, and absorbed doses are acceptable. The potential of (18)F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.
View details for DOI 10.2967/jnumed.117.192641
View details for PubMedID 28572487
Molecular imaging and biology
Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [(18)F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [(18)F]FTC-146.[(18)F]FTC-146 is prepared via a direct [(18)F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [(18)F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects.[(18)F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/μmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [(18)F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [(18)F]FTC-146 was observed in cortical bone and muscle.A reliable and automated radiosynthesis for providing routine clinical-grade [(18)F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.
View details for DOI 10.1007/s11307-017-1064-z
View details for PubMedID 28280965
Long-Delay Arterial Spin Labeling Provides More Accurate Cerebral Blood Flow Measurements in Moyamoya Patients: A Simultaneous Positron Emission Tomography/MRI Study.
2017; 48 (9): 2441–49
Arterial spin labeling (ASL) MRI is a promising, noninvasive technique to image cerebral blood flow (CBF) but is difficult to use in cerebrovascular patients with abnormal, long arterial transit times through collateral pathways. To be clinically adopted, ASL must first be optimized and validated against a reference standard in these challenging patient cases.We compared standard-delay ASL (post-label delay=2.025 seconds), multidelay ASL (post-label delay=0.7-3.0 seconds), and long-label long-delay ASL acquisitions (post-label delay=4.0 seconds) against simultaneous [15O]-positron emission tomography (PET) CBF maps in 15 Moyamoya patients on a hybrid PET/MRI scanner. Dynamic susceptibility contrast was performed in each patient to identify areas of mild, moderate, and severe time-to-maximum (Tmax) delays. Relative CBF measurements by each ASL scan in 20 cortical regions were compared with the PET reference standard, and correlations were calculated for areas with moderate and severe Tmax delays.Standard-delay ASL underestimated relative CBF by 20% in areas of severe Tmax delays, particularly in anterior and middle territories commonly affected by Moyamoya disease (P<0.001). Arterial transit times correction by multidelay acquisitions led to improved consistency with PET, but still underestimated CBF in the presence of long transit delays (P=0.02). Long-label long-delay ASL scans showed the strongest correlation relative to PET, and there was no difference in mean relative CBF between the modalities, even in areas of severe delays.Post-label delay times of ≥4 seconds are needed and may be combined with multidelay strategies for robust ASL assessment of CBF in Moyamoya disease.
View details for PubMedID 28765286
Image-derived input function estimation on a TOF-enabled PET/MR for cerebral blood flow mapping.
Journal of cerebral blood flow and metabolism
(15)O-H2O PET imaging is an accurate method to measure cerebral blood flow (CBF) but it requires an arterial input function (AIF). Historically, image-derived AIF estimation suffers from low temporal resolution, spill-in, and spill-over problems. Here, we optimized tracer dose on a time-of-flight PET/MR according to the acquisition-specific noise-equivalent count rate curve. An optimized dose of 850 MBq of (15)O-H2O was determined, which allowed sufficient counts to reconstruct a short time-frame PET angiogram (PETA) during the arterial phase. This PETA enabled the measurement of the extent of spill-over, while an MR angiogram was used to measure the true arterial volume for AIF estimation. A segment of the high cervical arteries outside the brain was chosen, where the measured spill-in effects were minimal. CBF studies were performed twice with separate [15O]-H2O injections in 10 healthy subjects, yielding values of 88 ± 16, 44 ± 9, and 58 ± 11 mL/min/100 g for gray matter, white matter, and whole brain, with intra-subject CBF differences of 5.0 ± 4.0%, 4.1 ± 3.3%, and 4.5 ± 3.7%, respectively. A third CBF measurement after the administration of 1 g of acetazolamide showed 35 ± 23%, 29 ± 20%, and 33 ± 22% increase in gray matter, white matter, and whole brain, respectively. Based on these findings, the proposed noninvasive AIF method provides robust CBF measurement with (15)O-H2O PET.
View details for DOI 10.1177/0271678X17691784
View details for PubMedID 28155582
Studying GABA Neurophysiology by Simultaneous [18F]Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy
NATURE PUBLISHING GROUP. 2016: S209
View details for Web of Science ID 000440365600366
Effects of common anesthetic agents on [F-18] flumazenil binding to the GABA(A) receptor
The availability of GABAA receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [(18)F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [(18)F]flumazenil to GABAA receptors in mice.Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [(18)F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [(18)F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.PET images showed persistence of high [(18)F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.Anesthesia has pronounced effects on the binding and blood-brain distribution of [(18)F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAA receptors involving the use of anesthesia.
View details for DOI 10.1186/s13550-016-0235-2
View details for Web of Science ID 000387828200001
Optimization of 15O-H2O dose for cerebral blood flow imaging on a time-of-flight PET/MR scanner
SOC NUCLEAR MEDICINE INC. 2016
View details for Web of Science ID 000442211003016
Cerebral Blood Flow Imaging with 15O-H2O PET/MR-Review and Workflow Optimization
SOC NUCLEAR MEDICINE INC. 2016
View details for Web of Science ID 000442211003172
Image-based arterial input function estimation for cerebral blood flow measurement on a PET/MR scanner
SOC NUCLEAR MEDICINE INC. 2016
View details for Web of Science ID 000442211002285
- PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2. Science translational medicine 2015; 7 (310): 310ra169-?
Clinical grade [F-18]FTC-146: Radiosynthesis of sigma-1 receptor ligand for human PET studies
WILEY-BLACKWELL. 2015: S253
View details for Web of Science ID 000369950200254
Routine Production of [F-18]Flumazenil from Iodonium Tosylate Using a Sample Pretreatment Method: a 2.5-Year Production Report
MOLECULAR IMAGING AND BIOLOGY
2014; 16 (5): 619–25
[(18)F]Flumazenil, which has the advantage of a longer half-life than [(11)C]flumazenil, is well known for determining of the central benzodiazepine receptor concentrations. However, [(18)F]flumazenil has not been widely used because fluctuating and relatively low yields render automatic production insufficient for routine and multicenter clinical trials. Here, we describe the results of a 2.5-year production study of [(18)F]flumazenil using an iodonium tosylate precursor, which allowed us to overcome the limitations of low and fluctuating radiochemical yields.We developed a clinically applicable production system by modifying a commercial synthesizer for the reliable and reproducible production of [(18)F]flumazenil for routine clinical studies. [(18)F]Flumazenil was prepared at 150 °C for 5 min in the presence of 4-methylphenyl-mazenil iodonium tosylate (4 mg), a radical scavenger (TEMPO, 1 mg), and [(18)F]KF/kryptofix 2.2.2 complex in N,N-dimethylformamide (1 ml). In the purification step, the final mixture was pretreated using different cartridges before performing high-performance liquid chromatography (HPLC) separation. Finally, we measured the radiochemical yield and performed quality-control assays on 94 batches.After carrying out additional purification before HPLC separation using a C18 plus Sep-Pak cartridge, the radiochemical yield of [(18)F]flumazenil increased from 34.4 ± 9.7 % (without the pretreatment, n = 24) to 53.4 ± 9.0 % (n = 94), and the lifetime of the semi-preparative column was five times that of the column without the C18 plus Sep-Pak cartridge. The mean-specific activity of [(18)F]flumazenil was 572 ± 116 GBq/μmol at the end of synthesis, and the radiochemical purity was more than 99 %, as determined by analytical HPLC and radio-TLC. [(18)F]Flumazenil prepared using this method satisfied all quality-control test standards and was highly stable for up to 6 h after preparation.The results of the 2.5-year production study using an iodonium tosylate precursor indicate that [(18)F]flumazenil has commercial and routine clinical applicability.
View details for DOI 10.1007/s11307-014-0738-z
View details for Web of Science ID 000342135800005
View details for PubMedID 24788440
Facile aromatic radiofluorination of [F-18]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity
ORGANIC & BIOMOLECULAR CHEMISTRY
2011; 9 (24): 8346–55
Aromatic radiofluorination of the diaryliodonium tosylate precursor with [(18)F]fluoride ions has been applied successfully to access [(18)F]flumazenil in high radiochemical yields of 67.2 ± 2.7% (decay corrected). The stability and reactivity of the diaryliodonium tosylate precursor plays a key role in increasing the production of (18)F-labelled molecules under the fluorine-18 labelling condition. Various conditions were explored for the preparation of [(18)F]flumazenil from different diaryliodonium tosylate precursors. Optimum incorporation of [(18)F]fluoride ions in the 4-methylphenyl-mazenil iodonium tosylate precursor (5f) was achieved at 150 °C for 5 min by utilizing 4 mg of the precursor, K(2.2.2)/K(2)CO(3) complex, and the radical scavenger in N,N-dimethylformamide. This approach was extended to a viable method for use in automated synthesis with a radiochemical yield of 63.5 ± 3.2% (decay corrected, n = 26) within 60.0 ± 1.1 min. [(18)F]Flumazenil was isolated by preparative HPLC after the reaction was conducted under improved conditions and exhibited sufficient specific activity of 370-450 GBq μmol(-1), with a radiochemical purity of >99%, which will be suitable for human PET studies.
View details for DOI 10.1039/c1ob06277h
View details for Web of Science ID 000297354100018
View details for PubMedID 22057475
Highly efficient production of [F-18]fallypride using small amounts of base concentration
APPLIED RADIATION AND ISOTOPES
2010; 68 (12): 2279–84
To minimize the base concentration of a phase-transfer catalyst, [(18)F]fluoride was extracted from (18)O-enriched water trapped on an activated ion exchange cartridge (Chromafix PS-HCO(3)) using different concentrations of tetrabutylammonium bicarbonate (TBAHCO(3)) or Kryptofix 2.2.2./K(2)CO(3) in organic solvents such as CH(3)CN/H(2)O or MeOH/H(2)O. The optimal labeling condition for [(18)F]fallypride with automated synthesis was that 2 mg of tosyl-fallypride in acetonitrile (1 mL) was heated at 100 degrees C for 10 min using 40% TBAHCO(3) (10 microL). [(18)F]Fallypride was obtained with a high radiochemical yield of approximately 68+/-1.6% (decay-corrected, n=42) with a total synthesis time of 51+/-1.2 min, including HPLC purification and solid-phase purification for the final formulation.
View details for DOI 10.1016/j.apradiso.2010.06.016
View details for Web of Science ID 000283384400027
View details for PubMedID 20609592
- Intensification of the KOTRON-13 Cyclotron by Optimizing the Ion Source JOURNAL OF THE KOREAN PHYSICAL SOCIETY 2010; 57 (6): 1376–80