Jun Hyung Park

All Publications

• PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84. JACS Au Kalita, M., Park, J. H., Kuo, R. C., Hayee, S., Marsango, S., Straniero, V., Alam, I. S., Rivera-Rodriguez, A., Pandrala, M., Carlson, M. L., Reyes, S. T., Jackson, I. M., Suigo, L., Luo, A., Nagy, S. C., Valoti, E., Milligan, G., Habte, F., Shen, B., James, M. L. 2023; 3 (12): 3297-3310

  Abstract

  Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.

  View details for DOI 10.1021/jacsau.3c00435

  View details for PubMedID 38155640

  View details for PubMedCentralID PMC10751761

• Clinical grade [<SUP>15</SUP>O]O₂ Production for Human Inhalation PET/MRI study Park, J., Kellow, R., Watkins, R., Zaharchuk, G., Fan, A., Shen, B. ELSEVIER SCIENCE INC. 2023: S105

  View details for Web of Science ID 001128725600141

• Development and initial evaluation of a novel 11C-labeled PET tracer to image GPR84 expressing-myeloid cells during neuroinflammation Kalita, M., Park, J., Hayee, S., Marsango, S., Carlson, M., Reyes, S., Nagy, S., Straniero, V., Pandrala, M., Jackson, I., Alam, I., Valoti, E., Milligan, G., Shen, B., James, M. SOC NUCLEAR MEDICINE INC. 2023

  View details for Web of Science ID 001109210200159

• Reductions in synaptic marker SV2A in early-course Schizophrenia. Journal of psychiatric research Yoon, J. H., Zhang, Z., Mormino, E., Davidzon, G., Minzenberg, M. J., Ballon, J., Kalinowski, A., Hardy, K., Naganawa, M., Carson, R. E., Khalighi, M., Park, J. H., Levinson, D. F., Chin, F. T. 2023; 161: 213-217

  Abstract

  Excess synaptic pruning during neurodevelopment has emerged as one of the leading hypotheses on the causal mechanism for schizophrenia. It proposes that excess synaptic elimination occurs during development before the formal onset of illness. Accordingly, synaptic deficits may be observable at all stages of illnesses, including in the early phases. The availability of [11C]UCB-J, the first-in-human in vivo synaptic marker, represents an opportunity for testing this hypothesis with a relatively high level of precision. The first two published [11C]UCB-J schizophrenia studies have documented significant, widespread reductions in binding in chronic patients. The present study tested the hypothesis that reductions are present in early-course patients. 18 subjects completed [11C]UCB-J PET scans, (nine with schizophrenia, average duration of illness of 3.36 years, and nine demographically-matched healthy individuals). We compared binding levels, quantified as non-displaceable specific binding (BPND), in a set of a priori-specified brain regions of interest (ROIs). Eight ROIs (left and right hippocampus, right superior temporal and Heschl's gyrus, left and right putamen, and right caudal and rostral middle frontal gyrus) showed large reductions meeting Bonferroni corrected significant levels, p<0.0036. Exploratory, atlas-wide analyses confirmed widespread reductions in schizophrenia. We also observed significant positive correlations between binding levels and cognitive performance and a negative correlation with the severity of delusions. These results largely replicate findings from chronic patients, indicating that extensive [11C]UCB-J binding deficits are reliable and reproducible. Moreover, these results add to the growing evidence that excess synaptic pruning is a major disease mechanism for schizophrenia.

  View details for DOI 10.1016/j.jpsychires.2023.02.026

  View details for PubMedID 36934603

• MRI quantification of brain oxygenation and relationship with cerebrovascular reactivity in Moyamoya disease using simultaneous [O-15]-water PET/MRI Fan, A. P., Chen, D., Shin, D. D., Zhao, M. Y., Park, J., Shen, B., Khalighi, M. M., Holley, D., Halbert, K., Steinberg, G. K., Zaharchuk, G. SAGE PUBLICATIONS INC. 2021: 64-65

  View details for Web of Science ID 000815523000045

• A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2 Induced Glycolytic Reprogramming in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Beinat, C., Patel, C. B., Haywood, T., Murty, S., Naya, L., Castillo, J. B., Reyes, S. T., Phillips, M., Buccino, P., Shen, B., Park, J. H., Koran, M. E., Alam, I. S., James, M. L., Holley, D., Halbert, K., Gandhi, H., He, J. Q., Granucci, M., Johnson, E., Liu, D. D., Uchida, N., Sinha, R., Chu, P., Born, D. E., Warnock, G. I., Weissman, I., Hayden Gephart, M., Khalighi, M. M., Massoud, T. F., Iagaru, A., Davidzon, G., Thomas, R., Nagpal, S., Recht, L. D., Gambhir, S. S. 2021

  Abstract

  PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients.EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 {plus minus} 29.58 GBq/mol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients.RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 {plus minus} 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [18F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation.CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

  View details for DOI 10.1158/1078-0432.CCR-21-0544

  View details for PubMedID 34475101

• Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy. Scientific reports Reyes, S. T., Deacon, R. M., Guo, S. G., Altimiras, F. J., Castillo, J. B., van der Wildt, B., Morales, A. P., Park, J. H., Klamer, D., Rosenberg, J., Oberman, L. M., Rebowe, N., Sprouse, J., Missling, C. U., McCurdy, C. R., Cogram, P., Kaufmann, W. E., Chin, F. T. 2021; 11 (1): 17150

  Abstract

  Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS' cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R's role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug's dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

  View details for DOI 10.1038/s41598-021-94079-7

  View details for PubMedID 34433831

• Cerebrovascular Reactivity Measurements Using Simultaneous 15O-Water PET and ASL MRI: Impacts of Arterial Transit Time, Labeling Efficiency, and Hematocrit. NeuroImage Zhao, M. Y., Fan, A. P., Chen, D. Y., Sokolska, M. J., Guo, J. n., Ishii, Y. n., Shin, D. D., Khalighi, M. M., Holley, D. n., Halbert, K. n., Otte, A. n., Williams, B. n., Rostami, T. n., Park, J. H., Shen, B. n., Zaharchuk, G. n. 2021: 117955

  Abstract

  Cerebrovascular reactivity (CVR) reflects the capacity of the brain to meet changing physiological demands and can predict the risk of cerebrovascular diseases. CVR can be obtained by measuring the change in cerebral blood flow (CBF) during a brain stress test where CBF is altered by a vasodilator such as acetazolamide. Although the gold standard to quantify CBF is PET imaging, the procedure is invasive and inaccessible to most patients. Arterial spin labeling (ASL) is a non-invasive and quantitative MRI method to measure CBF, and a consensus guideline has been published for the clinical application of ASL. Despite single post labeling delay (PLD) pseudo-continuous ASL (PCASL) being the recommended ASL technique for CBF quantification, it is sensitive to variations to the arterial transit time (ATT) and labeling efficiency induced by the vasodilator in CVR studies. Multi-PLD ASL controls for the changes in ATT, and velocity selective ASL is in theory insensitive to both ATT and labeling efficiency. Here we investigate CVR using simultaneous 15O-water PET and ASL MRI data from 19 healthy subjects. CVR and CBF measured by the ASL techniques were compared using PET as the reference technique. The impacts of blood T1 and labeling efficiency on ASL were assessed using individual measurements of hematocrit and flow velocity data of the carotid and vertebral arteries measured using phase-contrast MRI. We found that multi-PLD PCASL is the ASL technique most consistent with PET for CVR quantification (group mean CVR of the whole brain = 42±19% and 40±18% respectively). Single-PLD ASL underestimated the CVR of the whole brain significantly by 15±10% compared with PET (p<0.01, paired t test). Changes in ATT pre- and post-acetazolamide was the principal factor affecting ASL-based CVR quantification. Variations in labeling efficiency and blood T1 had negligible effects.

  View details for DOI 10.1016/j.neuroimage.2021.117955

  View details for PubMedID 33716155

• Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Molecular psychiatry Fung, L. K., Flores, R. E., Gu, M. n., Sun, K. L., James, D. n., Schuck, R. K., Jo, B. n., Park, J. H., Lee, B. C., Jung, J. H., Kim, S. E., Saggar, M. n., Sacchet, M. D., Warnock, G. n., Khalighi, M. M., Spielman, D. n., Chin, F. T., Hardan, A. Y. 2020

  Abstract

  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

• 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 Ishii, Y., Thamm, T., Guo, J., Khalighi, M., Wardak, M., Holley, D., Gandhi, H., Park, J., Shen, B., Steinberg, G. K., Chin, F. T., Zaharchuk, G., Fan, A. 2020; 51 (1): 183–94

  View details for DOI 10.1002/jmri.26773

  View details for Web of Science ID 000530627200018

• Carbon-11 labeled BLZ945 as PET tracer for Colony Stimulating Factor 1 Receptor imaging in the brain van der Wildt, B., Miao, Z., Park, J., Reyes, S., Klockow, J., Shen, B., Chin, F. 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 Fan, A. P., Khalighi, M. M., Guo, J., Ishii, Y., Rosenberg, J., Wardak, M., Park, J., Shen, B., Holley, D., Gandhi, H., Haywood, T., Singh, P., Steinberg, G. K., Chin, F. T., Zaharchuk, G. 2019; 50 (2): 373–80

  View details for DOI 10.1161/STROKEAHA.118.023426

  View details for Web of Science ID 000469346800028

• 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 Ishii, Y. n., Thamm, T. n., Guo, J. n., Khalighi, M. M., Wardak, M. n., Holley, D. n., Gandhi, H. n., Park, J. H., Shen, B. n., Steinberg, G. K., Chin, F. T., Zaharchuk, G. n., Fan, A. P. 2019

  Abstract

  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. Translational psychiatry Hamilton, J. P., Sacchet, M. D., Hjornevik, T., Chin, F. T., Shen, B., Kampe, R., Park, J. H., Knutson, B. D., Williams, L. M., Borg, N., Zaharchuk, G., Camacho, M. C., Mackey, S., Heilig, M., Drevets, W. C., Glover, G. H., Gambhir, S. S., Gotlib, I. H. 2018; 8 (1): 264

  Abstract

  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 Beinat, C., Patel, C., Murty, S., Haywood, T., Park, J., Xie, Y., Gambhir, S. OXFORD UNIV PRESS INC. 2018: 34

  View details for Web of Science ID 000460646300129

• F-FTC-146 in humans. Journal of nuclear medicine Hjørnevik, T., Cipriano, P. W., Shen, B., Hyung Park, J., Gulaka, P., Holley, D., Gandhi, H., Yoon, D., Mittra, E. S., Zaharchuk, G., Gambhir, S. S., McCurdy, C. R., Chin, F. T., Biswal, S. 2017

  Abstract

  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

• F]FTC-146. Molecular imaging and biology Shen, B., Park, J. H., Hjørnevik, T., Cipriano, P. W., Yoon, D., Gulaka, P. K., Holly, D., Behera, D., Avery, B. A., Gambhir, S. S., McCurdy, C. R., Biswal, S., Chin, F. T. 2017

  Abstract

  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. Stroke Fan, A. P., Guo, J. n., Khalighi, M. M., Gulaka, P. K., Shen, B. n., Park, J. H., Gandhi, H. n., Holley, D. n., Rutledge, O. n., Singh, P. n., Haywood, T. n., Steinberg, G. K., Chin, F. T., Zaharchuk, G. n. 2017; 48 (9): 2441–49

  Abstract

  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 Khalighi, M. M., Deller, T. W., Fan, A. P., Gulaka, P. K., Shen, B., Singh, P., Park, J., Chin, F. T., Zaharchuk, G. 2017: 271678X17691784-?

  Abstract

  (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 Fung, L., Gu, M., Leuze, C., Hjoernevik, T., Shen, B., Park, J., Flores, R., Reyes, S., Holley, D., Gandhi, H., Jung, J., Lee, B., Kim, S., Khalighi, M., Gulaka, P., Zaharchuk, G., McNab, J., Quon, A., Spielman, D., Chin, F. 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 EJNMMI RESEARCH Palner, M., Beinat, C., Banister, S., Zanderigo, F., Park, J. H., Shen, B., Hjoernevik, T., Jung, J. H., Lee, B. C., Kim, S. E., Fung, L., Chin, F. T. 2016; 6

  Abstract

  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 Deller, T., Khalighi, M., Fan, A., Singh, P., Park, J., Hoehne, A., Shen, B., Chin, F., Zaharchuk, G. 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 Gandhi, H., Holley, D., Fan, A., Gulaka, P., Mittra, E., Shen, B., Singh, P., Park, J., Chin, F., Zaharchuk, G. 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 Khalighi, M., Fan, A., Delso, G., Singh, P., Park, J., Hoehne, A., Shen, B., Chin, F., Zaharchuk, G. 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 Witney, T. H., James, M. L., Shen, B., Chang, E., Pohling, C., Arksey, N., Hoehne, A., Shuhendler, A., Park, J., Bodapati, D., Weber, J., Gowrishankar, G., Rao, J., Chin, F. T., Gambhir, S. S. 2015; 7 (310): 310ra169-?

  View details for DOI 10.1126/scitranslmed.aac6117

  View details for PubMedID 26491079

• Clinical grade [F-18]FTC-146: Radiosynthesis of sigma-1 receptor ligand for human PET studies Shen, B., Park, J., Arksey, N. C., McCurdy, C. R., Chin, F. T. 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 Moon, B., Park, J., Lee, H., Lee, B., Kim, S. 2014; 16 (5): 619–25

  Abstract

  [(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 Moon, B., Kil, H., Park, J., Kim, J., Park, J., Chi, D., Lee, B., Kim, S. 2011; 9 (24): 8346–55

  Abstract

  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 Moon, B., Park, J., Lee, H., Kim, J., Kil, H., Lee, B., Chi, D., Lee, B., Kim, Y., Kim, S. 2010; 68 (12): 2279–84

  Abstract

  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 Lee, B., Lee, H., Park, J., Moon, B., Kim, S., Lee, W., Jung, K., Chae, S., Km, J. 2010; 57 (6): 1376–80

  View details for DOI 10.3938/jkps.57.1376

  View details for Web of Science ID 000285486100008