Honors & Awards

  • Roland H. Thorp Prize in Pharmacology, - (2003)
  • Dean’s Honour List, - (2003)
  • First Class Honours in Pharmacology, - (2004)
  • University Medal, The University of Sydney (2004)
  • Travel Award, International Symposium on Radiopharmaceutical Sciences - Iowa, USA, - (2005)
  • Best Oral Presentation Award, Royal Australian Chemistry Institute Drug Design Conference, - (2006)
  • Travel Award, International Symposium on Radiopharmaceutical Sciences - Aachen, Germany, - (2007)
  • Australian Postgraduate Award, - (2005-2008)
  • John A Lamberton Research Scholarship, - (2005-2008)
  • Travel Award, World Molecular Imaging Congress - Kyoto, Japan, - (2010)
  • Travel Fellowship, Alzheimer's Association International Conference - Boston, USA, - (2013)
  • Poster Presentation Award, World Molecular Imaging Congress - Savannah, Georgia, - (2013)
  • First Prize Poster & Abstract Award, TSPO Symposium on Microglia Imaging & Biology - Manchester, UK, - (2014)
  • Alavi-Mandell Award, Society of Nuclear Medicine and Molecular Imaging (2015)
  • Suffrage Science Award, - (2016)

Professional Education

  • Ph.D., University of Sydney, Pharmacology (2008)
  • B.S., University of Sydney, Pharmacology/Medicinal Chemistry (2004)

Research & Scholarship

Current Research and Scholarly Interests

My research is on developing and evaluating molecular imaging agents to improve the way we diagnose, treat, and understand brain diseases, with a particular focus on Alzheimer's disease (AD).

I am very interested in imaging neuroinflammation and neurodegeneration using positron emission tomography (PET). Non-invasive PET imaging of these processes will likely enhance our understanding of a range of brain disorders (including Alzheimer’s disease, multiple sclerosis, and stroke), and ultimately generate effective diagnostic and treatment strategies.

For over a decade, my research has involved designing and developing novel PET radioligands for different neurological targets, including the translocator protein (18kDa) (TSPO). Since TSPO expression reflects glial activation and neuroinflammation, radioligands for this protein may act as valuable tools for detecting regions of active brain disease before clinical signs manifest. These radioligands may also be used to track disease progression and monitor response to novel therapeutics.


Stanford Advisees


All Publications

  • Further validation to support clinical translation of [(18)F]FTC-146 for imaging sigma-1 receptors. EJNMMI research Shen, B., James, M. L., Andrews, L., Lau, C., Chen, S., Palner, M., Miao, Z., Arksey, N. C., Shuhendler, A. J., Scatliffe, S., Kaneshige, K., Parsons, S. M., McCurdy, C. R., Salehi, A., Gambhir, S. S., Chin, F. T. 2015; 5 (1): 49-?


    This study aims to further evaluate the specificity and selectivity of [(18)F]FTC-146 and obtain additional data to support its clinical translation.The binding of [(19)F]FTC-146 to vesicular acetylcholine transporter (VAChT) was evaluated using [(3)H]vesamicol and PC12(A123.7) cells in an in vitro binding assay. The uptake and kinetics of [(18)F]FTC-146 in S1R-knockout mice (S1R-KO) compared to wild-type (WT) littermates was assessed using dynamic positron emission tomography (PET) imaging. Ex vivo autoradiography and histology were conducted using a separate cohort of S1R-KO/WT mice, and radiation dosimetry was calculated from WT mouse data (extrapolated for human dosing). Toxicity studies in Sprague-Dawley rats were performed with a dose equivalent to 250× the anticipated clinical dose of [(19)F]FTC-146 mass.VAChT binding assay results verified that [(19)F]FTC-146 displays negligible affinity for VAChT (K i = 450 ± 80 nM) compared to S1R. PET images demonstrated significantly higher tracer uptake in WT vs. S1R-KO brain (4.57 ± 1.07 vs. 1.34 ± 0.4 %ID/g at 20-25 min, n = 4, p < 0.05). In S1R-KO mice, it was shown that rapid brain uptake and clearance 10 min post-injection, which are consistent with previous S1R-blocking studies in mice. Three- to fourfold higher tracer uptake was observed in WT relative to S1R-KO mouse brains by ex vivo autoradiography. S1R staining coincided well with the autoradiographic data in all examined brain regions (r (2) = 0.85-0.95). Biodistribution results further demonstrated high [(18)F]FTC-146 accumulation in WT relative to KO mouse brain and provided quantitative information concerning tracer uptake in S1R-rich organs (e.g., heart, lung, pancreas) for WT mice vs. age-matched S1R-KO mice. The maximum allowed dose per scan in humans as extrapolated from mouse dosimetry was 33.19 mCi (1228.03 MBq). No significant toxicity was observed even at a 250X dose of the maximum carrier mass [(19)F]FTC-146 expected to be injected for human studies.Together, these data indicate that [(18)F]FTC-146 binds specifically to S1Rs and is a highly promising radiotracer ready for clinical translation to investigate S1R-related diseases.

    View details for DOI 10.1186/s13550-015-0122-2

    View details for PubMedID 26384292

  • 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-?


    Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of metabolic precursors. We report here the synthesis and evaluation of a positron emission tomography (PET) radiotracer, [(11)C]DASA-23, that provides a direct noninvasive measure of PKM2 expression in preclinical models of glioblastoma multiforme (GBM). In vivo, orthotopic U87 and GBM39 patient-derived tumors were clearly delineated from the surrounding normal brain tissue by PET imaging, corresponding to exclusive tumor-associated PKM2 expression. In addition, systemic treatment of mice with the PKM2 activator TEPP-46 resulted in complete abrogation of the PET signal in intracranial GBM39 tumors. Together, these data provide the basis for the clinical evaluation of imaging agents that target this important gatekeeper of tumor glycolysis.

    View details for DOI 10.1126/scitranslmed.aac6117

    View details for PubMedID 26491079

  • Microglial Malfunction: The Third Rail in the Development of Alzheimer's Disease TRENDS IN NEUROSCIENCES Mhatre, S. D., Tsai, C. A., Rubin, A. J., James, M. L., Andreasson, K. I. 2015; 38 (10): 621-636


    Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-β (Aβ) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Aβ accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Aβ pathology.

    View details for DOI 10.1016/j.tins.2015.08.006

    View details for Web of Science ID 000363347400006

    View details for PubMedID 26442696

  • PET Imaging of Translocator Protein (18 kDa) in a Mouse Model of Alzheimer's Disease Using N-(2,5-Dimethoxybenzyl)-2-F-18-Fluoro-N-(2-Phenoxyphenyl)Acetamide JOURNAL OF NUCLEAR MEDICINE James, M. L., Belichenko, N. P., Nguyen, T. V., Andrews, L. E., Ding, Z., Liu, H., Bodapati, D., Arksey, N., Shen, B., Cheng, Z., Wyss-Coray, T., Gambhir, S. S., Longo, F. M., Chin, F. T. 2015; 56 (2): 311-316


    Herein we aimed to evaluate the utility of N-(2,5-dimethoxybenzyl)-2-(18)F-fluoro-N-(2-phenoxyphenyl)acetamide ((18)F-PBR06) for detecting alterations in translocator protein (TSPO) (18 kDa), a biomarker of microglial activation, in a mouse model of Alzheimer's disease (AD).Wild-type (wt) and AD mice (i.e., APP(L/S)) underwent (18)F-PBR06 PET imaging at predetermined time points between the ages of 5-6 and 15-16 mo. MR images were fused with PET/CT data to quantify (18)F-PBR06 uptake in the hippocampus and cortex. Ex vivo autoradiography and TSPO/CD68 immunostaining were also performed using brain tissue from these mice.PET images showed significantly higher accumulation of (18)F-PBR06 in the cortex and hippocampus of 15- to 16-mo-old APP(L/S) mice than age-matched wts (cortex/muscle: 2.43 ± 0.19 vs. 1.55 ± 0.15, P < 0.005; hippocampus/muscle: 2.41 ± 0.13 vs. 1.55 ± 0.12, P < 0.005). And although no significant difference was found between wt and APP(L/S) mice aged 9-10 mo or less using PET (P = 0.64), we were able to visualize and quantify a significant difference in (18)F-PBR06 uptake in these mice using autoradiography (cortex/striatum: 1.13 ± 0.04 vs. 0.96 ± 0.01, P < 0.05; hippocampus/striatum: 1.266 ± 0.003 vs. 1.096 ± 0.017, P < 0.001). PET results for 15- to 16-mo-old mice correlated well with autoradiography and immunostaining (i.e., increased (18)F-PBR06 uptake in brain regions containing elevated CD68 and TSPO staining in APP(L/S) mice, compared with wts).(18)F-PBR06 shows great potential as a tool for visualizing TSPO/microglia in the progression and treatment of AD.

    View details for DOI 10.2967/jnumed.114.141648

    View details for Web of Science ID 000349324300035

    View details for PubMedID 25613536

  • Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation JOURNAL OF EXPERIMENTAL MEDICINE Ding, Z., Mathur, V., Ho, P. P., James, M. L., Lucin, K. M., Hoehne, A., Alabsi, H., Gambhir, S. S., Steinman, L., Luo, J., Wyss-Coray, T. 2014; 211 (2): 189-198


    Aberrant microglial responses contribute to neuroinflammation in many neurodegenerative diseases, but no current therapies target pathogenic microglia. We discovered unexpectedly that the antiviral drug ganciclovir (GCV) inhibits the proliferation of microglia in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), as well as in kainic acid-induced excitotoxicity. In EAE, GCV largely prevented infiltration of T lymphocytes into the central nervous system (CNS) and drastically reduced disease incidence and severity when delivered before the onset of disease. In contrast, GCV treatment had minimal effects on peripheral leukocyte distribution in EAE and did not inhibit generation of antibodies after immunization with ovalbumin. Additionally, a radiolabeled analogue of penciclovir, [(18)F]FHBG, which is similar in structure to GCV, was retained in areas of CNS inflammation in EAE, but not in naive control mice, consistent with the observed therapeutic effects. Our experiments suggest GCV may have beneficial effects in the CNS beyond its antiviral properties.

    View details for DOI 10.1084/jem.20120696

    View details for Web of Science ID 000331281600002

    View details for PubMedID 24493798

  • PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [F-18]PBR06 MOLECULAR IMAGING AND BIOLOGY Lartey, F. M., Ahn, G., Shen, B., Cord, K., Smith, T., Chua, J. Y., Rosenblum, S., Liu, H., James, M. L., Chernikova, S., Lee, S. W., Pisani, L. J., Tirouvanziam, R., Chen, J. W., Palmer, T. D., Chin, F. T., Guzman, R., Graves, E. E., Loo, B. W. 2014; 16 (1): 109-117


    The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [(18)F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([(18)F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model.Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography.[(18)F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [(18)F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET.[(18)F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.

    View details for DOI 10.1007/s11307-013-0664-5

    View details for Web of Science ID 000329793200014

    View details for PubMedID 23836504

  • Evaluation of s-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Shen, B., Nielsen, C. H., Behera, D., Buckmaster, C. L., Mesangeau, C., Zavaleta, C., Vuppala, P. K., Jamalapuram, S., Avery, B. A., Lyons, D. M., McCurdy, C. R., Biswal, S., Gambhir, S. S., Chin, F. T. 2014; 55 (1): 147-153


    The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

    View details for DOI 10.2967/jnumed.113.120261

    View details for PubMedID 24337599

  • A F-18-Labeled Saxitoxin Derivative for in Vivo PET-MR Imaging of Voltage-Gated Sodium Channel Expression Following Nerve Injury JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hoehne, A., Behera, D., Parsons, W. H., James, M. L., Shen, B., Borgohain, P., Bodapati, D., Prabhakar, A., Gambhir, S. S., Yeomans, D. C., Biswal, S., Chin, F. T., Du Bois, J. 2013; 135 (48): 18012-18015


    Both chronic and neuropathic pain conditions are associated with increased expression of certain voltage-gated sodium ion channel (NaV) isoforms in peripheral sensory neurons. A method for noninvasive imaging of these channels could represent a powerful tool for investigating aberrant expression of NaV and its role in pain pathogenesis. Herein, we describe the synthesis and evaluation of a positron emission tomography (PET) radiotracer targeting NaVs, the design of which is based on the potent, NaV-selective inhibitor saxitoxin. Both autoradiography analysis of sciatic nerves excised from injured rats as well as whole animal PET-MR imaging demonstrate that a systemically administered [(18)F]-labeled saxitoxin derivative concentrates at the site of nerve injury, consistent with upregulated sodium channel expression following axotomy. This type of PET agent has potential use for serial monitoring of channel expression levels at injured nerves throughout wound healing and/or following drug treatment. Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation.

    View details for DOI 10.1021/ja408300e

    View details for Web of Science ID 000328100000002

  • Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival JOURNAL OF EXPERIMENTAL MEDICINE Luo, J., Elwood, F., Britschgi, M., Villeda, S., Zhang, H., Ding, Z., Zhu, L., Alabsi, H., Getachew, R., Narasimhan, R., Wabl, R., Fainberg, N., James, M. L., Wong, G., Relton, J., Gambhir, S. S., Pollard, J. W., Wyss-Coray, T. 2013; 210 (1): 157-172


    Colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34) are functional ligands of the CSF1 receptor (CSF1R) and thus are key regulators of the monocyte/macrophage lineage. We discovered that systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer's disease. CSF1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in wild-type mice when administered systemically before or up to 6 h after injury. These effects were accompanied by maintenance of cAMP responsive element-binding protein (CREB) signaling in neurons rather than in microglia. Using lineage-tracing experiments, we discovered that a small number of neurons in the hippocampus and cortex express CSF1R under physiological conditions and that kainic acid-induced excitotoxic injury results in a profound increase in neuronal receptor expression. Selective deletion of CSF1R in forebrain neurons in mice exacerbated excitotoxin-induced death and neurodegeneration. We conclude that CSF1 and IL-34 provide powerful neuroprotective and survival signals in brain injury and neurodegeneration involving CSF1R expression on neurons.

    View details for DOI 10.1084/jem.20120412

    View details for Web of Science ID 000313560900014

  • Integrin-Targeted Molecular Imaging of Experimental Abdominal Aortic Aneurysms by 18F-labeled Arg-Gly-Asp Positron-Emission Tomography CIRCULATION: CARDIOVASCULAR IMAGING Kitagawa, T., Kosuge, H., Chang, E., James, M. L., Yamamoto, T., Shen, B., Chin, F. T., Gambhir, S. S., Dalman, R. L., McConnell, M. V. 2013; 1 (6): 950-956
  • New Positron Emission Tomography (PET) Radioligand for Imaging sigma-1 Receptors in Living Subjects JOURNAL OF MEDICINAL CHEMISTRY James, M. L., Shen, B., Zavaleta, C. L., Nielsen, C. H., Mesangeau, C., Vuppala, P. K., Chan, C., Avery, B. A., Fishback, J. A., Matsumoto, R. R., Gambhir, S. S., McCurdy, C. R., Chin, F. T. 2012; 55 (19): 8272-8282


    ?-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([(18)F]FTC-146, [(18)F]13). [(18)F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/?mol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [(18)F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [(18)F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [(18)F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [(18)F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.

    View details for DOI 10.1021/jm300371c

    View details for Web of Science ID 000309643500008

    View details for PubMedID 22853801



    Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.

    View details for DOI 10.1152/physrev.00049.2010

    View details for Web of Science ID 000306562500009

    View details for PubMedID 22535898

  • Preclinical Evaluation of Raman Nanoparticle Biodistribution for their Potential Use in Clinical Endoscopy Imaging SMALL Zavaleta, C. L., Hartman, K. B., Miao, Z., James, M. L., Kempen, P., Thakor, A. S., Nielsen, C. H., Sinclair, R., Cheng, Z., Gambhir, S. S. 2011; 7 (15): 2232-2240


    Raman imaging offers unsurpassed sensitivity and multiplexing capabilities. However, its limited depth of light penetration makes direct clinical translation challenging. Therefore, a more suitable way to harness its attributes in a clinical setting would be to couple Raman spectroscopy with endoscopy. The use of an accessory Raman endoscope in conjunction with topically administered tumor-targeting Raman nanoparticles during a routine colonoscopy could offer a new way to sensitively detect dysplastic lesions while circumventing Raman's limited depth of penetration and avoiding systemic toxicity. In this study, the natural biodistribution of gold surface-enhanced Raman scattering (SERS) nanoparticles is evaluated by radiolabeling them with (64) Cu and imaging their localization over time using micropositron emission tomography (PET). Mice are injected either intravenously (IV) or intrarectally (IR) with approximately 100 microcuries (?Ci) (3.7 megabecquerel (MBq)) of (64) Cu-SERS nanoparticles and imaged with microPET at various time points post injection. Quantitative biodistribution data are obtained as % injected dose per gram (%ID g(-1)) from each organ, and the results correlate well with the corresponding microPET images, revealing that IV-injected mice have significantly higher uptake (p < 0.05) in the liver (5 h = 8.96% ID g(-1); 24 h = 8.27% ID g(-1)) than IR-injected mice (5 h = 0.09% ID g(-1); 24 h = 0.08% ID g(-1)). IR-injected mice show localized uptake in the large intestine (5 h = 10.37% ID g(-1); 24 h = 0.42% ID g(-1)) with minimal uptake in other organs. Raman imaging of excised tissues correlate well with biodistribution data. These results suggest that the topical application of SERS nanoparticles in the mouse colon appears to minimize their systemic distribution, thus avoiding potential toxicity and supporting the clinical translation of Raman spectroscopy as an endoscopic imaging tool.

    View details for DOI 10.1002/smll.201002317

    View details for Web of Science ID 000294361200015

    View details for PubMedID 21608124

  • [C-11]-DPA-713 and [F-18]-DPA-714 as New PET Tracers for TSPO: A Comparison with [C-11]-(R)-PK11195 in a Rat Model of Herpes Encephalitis MOLECULAR IMAGING AND BIOLOGY Doorduin, J., Klein, H. C., Dierckx, R. A., James, M., Kassiou, M., De Vries, E. F. 2009; 11 (6): 386-398


    Activation of microglia cells plays an important role in neurological diseases. Positron emission tomography (PET) with [(11)C]-(R)-PK11195 has already been used to visualize activated microglia cells in neurological diseases. However, [(11)C]-(R)-PK11195 may not possess the required sensitivity to visualize mild neuroinflammation. In this study, we evaluated the PET tracers [(11)C]-DPA-713 and [(18)F]-DPA-714 as agents for imaging of activated microglia in a rat model of herpes encephalitis.Rats were intranasally inoculated with HSV-1. On day 6 or 7 after inoculation, small animal PET studies were performed to compare [(11)C]-(R)-PK11195, [(11)C]-DPA-713, and [(18)F]-DPA-714.Uptake of [(11)C]-DPA-713 in infected brain areas was comparable to that of [(11)C]-(R)-PK11195, but [(11)C]-DPA-713 showed lower non-specific binding. Non-specific uptake of [(18)F]-DPA-714 was lower than that of [(11)C]-(R)-PK11195. In the infected brain, total [(18)F]-DPA-714 uptake was lower than that of [(11)C]-(R)-PK11195, with comparable specific uptake.[(11)C]-DPA-713 may be more suitable for visualizing mild inflammation than [(11)C]-(R)-PK11195. In addition, the fact that [(18)F]-DPA-714 is an agonist PET tracer opens new possibilities to evaluate different aspects of neuroinflammation. Therefore, both tracers warrant further investigation in animal models and in a clinical setting.

    View details for DOI 10.1007/s11307-009-0211-6

    View details for Web of Science ID 000270882900002

    View details for PubMedID 19330384

  • Initial Evaluation of C-11-DPA-713, a Novel TSPO PET Ligand, in Humans JOURNAL OF NUCLEAR MEDICINE Endres, C. J., Pomper, M. G., James, M., Uzuner, O., Hammoud, D. A., Watkins, C. C., Reynolds, A., Hilton, J., Dannals, R. F., Kassiou, M. 2009; 50 (8): 1276-1282


    Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, (11)C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide ((11)C-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of (11)C-DPA-713 in human subjects using PET.Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity (11)C-DPA-713. For comparison, 2 additional healthy controls were studied with (11)C-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time-activity curves were fitted using 1- and 2-tissue-compartment models, with goodness-of-fit tests showing a preference for the 2-tissue model.In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for (11)C-R-PK11195. Accordingly, dose-normalized time-activity curves showed that (11)C-DPA-713 gives a larger brain signal.Studies in patient populations will help determine whether (11)C-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that (11)C-DPA-713 is a promising ligand for evaluating TSPO binding with PET.

    View details for DOI 10.2967/jnumed.109.062265

    View details for Web of Science ID 000272548100018

    View details for PubMedID 19617321

  • Comparative Evaluation of the Translocator Protein Radioligands C-11-DPA-713, F-18-DPA-714, and C-11-PK11195 in a Rat Model of Acute Neuroinflammation JOURNAL OF NUCLEAR MEDICINE Chauveau, F., Van Camp, N., Dolle, F., Kuhnast, B., Hinnen, F., Damont, A., Boutin, H., James, M., Kassiou, M., Tavitian, B. 2009; 50 (3): 468-476


    Overexpression of the translocator protein, TSPO (18 kDa), formerly known as the peripheral benzodiazepine receptor, is a hallmark of activation of cells of monocytic lineage (microglia and macrophages) during neuroinflammation. Radiolabeling of TSPO ligands enables the detection of neuroinflammatory lesions by PET. Two new radioligands, (11)C-labeled N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl]acetamide (DPA-713) and (18)F-labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl)acetamide (DPA-714), both belonging to the pyrazolopyrimidine class, were compared in vivo and in vitro using a rodent model of neuroinflammation.(11)C-DPA-713 and (18)F-DPA-714, as well as the classic radioligand (11)C-labeled (R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intrastriatal injection of (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionique gave rise to a strong neuroinflammatory response. Comparative endpoints included in vitro autoradiography and in vivo imaging on a dedicated small-animal PET scanner under identical conditions.(11)C-DPA-713 and (18)F-DPA-714 could specifically localize the neuroinflammatory site with a similar signal-to-noise ratio in vitro. In vivo, (18)F-DPA-714 performed better than (11)C-DPA-713 and (11)C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential.(18)F-DPA-714 appears to be an attractive alternative to (11)C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with (18)F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. (18)F-DPA-714 will be further evaluated in longitudinal studies of neuroinflammatory conditions such as are encountered in stroke or neurodegenerative diseases.

    View details for DOI 10.2967/jnumed.108.058669

    View details for Web of Science ID 000264084500027

    View details for PubMedID 19223401

  • Radiosynthesis of [F-18]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Damont, A., Hinnen, F., Kuhnast, B., Schollhorn-Peyronneau, M., James, M., Luus, C., Tavitian, B., Kassiou, M., Dolle, F. 2008; 51 (7-8): 286-292

    View details for DOI 10.1002/jlcr.1523

    View details for Web of Science ID 000258903500002

  • DPA-714, a new translocator protein-specific ligand: Synthesis, radiofluorination, and pharmacologic characterization JOURNAL OF NUCLEAR MEDICINE James, M. L., Fulton, R. R., Vercoullie, J., Henderson, D. J., Garreau, L., Chalon, S., Dolle, F., Selleri, S., Guilloteau, D., Kassiou, M. 2008; 49 (5): 814-822


    The translocator protein (18 kDa) (TSPO), formerly known as the peripheral benzodiazepine receptor, is dramatically upregulated under pathologic conditions. Activated microglia are the main cell type expressing the TSPO at sites of central nervous system pathology. Radioligands for the TSPO can therefore measure active disease in the brain. This article details the synthesis, radiofluorination, and pharmacologic evaluation of a new TSPO-specific pyrazolopyrimidine, DPA-714.The affinity of DPA-714 for the TSPO was measured in rat kidney membranes with (3)H-PK11195. The in vitro functional activity of DPA-714 was measured in a steroidogenic assay in which the ability of DPA-714 to increase pregnenolone synthesis was measured with rat C6 glioma cells. The radiofluorination of DPA-714 was achieved by nucleophilic (18)F-fluoride displacement of the tosylate precursor. (18)F-DPA-714 was assessed in rats harboring unilateral quinolinic acid (QA) lesions. In addition, pretreatment experiments were performed with PK11195 (5 mg/kg), DPA-714 (1 mg/kg), and DPA-713 (1 mg/kg). The in vivo binding and biodistribution of (18)F-DPA-714 were determined in a baboon with PET. Experiments involving presaturation with PK11195 (1.5 mg/kg) and displacement with DPA-714 (1 mg/kg) were conducted to evaluate the specificity of radioligand binding.In vitro binding studies revealed that DPA-714 displayed a high affinity for the TSPO (dissociation constant, 7.0 nM). DPA-714 stimulated pregnenolone synthesis at levels 80% above the baseline. (18)F-DPA-714 was prepared at a 16% radiochemical yield and a specific activity of 270 GBq/mumol. In rats harboring unilateral QA lesions, an 8-fold-higher level of uptake of (18)F-DPA-714 was observed in the ipsilateral striatum than in the contralateral striatum. Uptake in the ipsilateral striatum was shown to be selective because it was inhibited to the level in the contralateral striatum in the presence of PK11195, nonlabeled DPA-714, or DPA-713. PET studies demonstrated rapid penetration and good retention of (18)F-DPA-714 in the baboon brain. Pretreatment with PK11195 effectively inhibited the uptake of (18)F-DPA-714 in the whole brain, indicating its selective binding to the TSPO. The injection of nonlabeled DPA-714 20 min after the injection of (18)F-DPA-714 resulted in radioligand washout, demonstrating the reversibility of (18)F-DPA-714 binding.(18)F-DPA-714 is a specific radioligand for the TSPO, displaying promising in vivo properties and thus warranting further investigation.

    View details for DOI 10.2967/jnumed.107.046151

    View details for Web of Science ID 000255809100033

    View details for PubMedID 18413395

  • C-11-DPA-713: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation JOURNAL OF NUCLEAR MEDICINE Boutin, H., Chauveau, F., Thominiaux, C., Gregoire, M., James, M. L., Trebossen, R., Hantraye, P., Dolle, F., Tavitian, B., Kassiou, M. 2007; 48 (4): 573-581


    The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration.We compared PK11195, the reference compound for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using (11)C-PK11195 or (11)C-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as (3)H-PK11195 autoradiographic studies were then correlated with the imaging data.Seven days after a unilateral injection of AMPA in the striatum, (11)C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than (11)C-PK11195 (2.5-fold +/- 0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)C-DPA-713 and (11)C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, (11)C-DPA-713 uptake was significantly lower than (11)C-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for (11)C-DPA-713 than for (11)C-PK11195.(11)C-DPA-713 displays a higher signal-to-noise ratio than (11)C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of (11)C-DPA-713. Although further studies in humans are required, (11)C-DPA-713 represents a suitable alternative to (11)C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.

    View details for DOI 10.2967/jnumed.106.036764

    View details for Web of Science ID 000245647000020

    View details for PubMedID 17401094

  • Development of Ligands for the Peripheral Benzodiazepine Receptor CURRENT MEDICINAL CHEMISTRY James, M. L., Selleri, S., Kassiou, M. 2006; 13 (17): 1991-2001


    The peripheral benzodiazepine receptor (PBR) initially characterised as a high affinity binding site for diazepam, is densely distributed in most peripheral organs whilst only moderately expressed in the healthy brain. The predominant cell type expressing the PBR at regions of central nervous system (CNS) pathology are activated microglial cells. Under neuroinflammatory conditions there is an over-expression of PBR binding sites indicating that measurements of PBR density can act as a useful index of brain disease activity. The PBR is now considered a significant therapeutic and diagnostic target which has provided the impetus for PBR ligand development. There are several classes of PBR ligands available including benzodiazepines (Ro5-4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106) and pyrazolopyrimidines (DPA-713). Subsequent conformationally restrained isoquinoline and indoleacetamide analogues have been synthesised in an attempt to yield PBR ligands with superior affinity and brain kinetics. Even though the PBR has been linked to a number of biochemical processes, including cell proliferation, apoptosis, steroidogenesis, porphyrin transport and immunomodulation, its exact physiological role is yet to be deciphered. Selective PBR ligands with favourable in vivo binding properties and kinetics is required to gain a more complete understanding on the normal functioning of the PBR and the chemical pathways underlying several pathological conditions. Novel PBR ligands with unique binding properties and functional activity may also generate information on the localisation of the PBR and the possibility of PBR subtypes. This review highlights the main classes of PBR ligands to date. In addition the biological activity and therapeutic potential of certain PBR ligands is discussed.

    View details for Web of Science ID 000207523900003

    View details for PubMedID 16842193

  • Improved synthesis of the peripheral benzodiazepine receptor ligand [C-11]DPA-713 using [C-11]methyl triflate APPLIED RADIATION AND ISOTOPES Thominiaux, C., Dolle, F., James, M. L., Bramoulle, Y., Boutin, H., Besret, L., Gregoire, M. C., Valette, H., Bottlaender, M., Tavitian, B., Hantraye, P., Selleri, S., Kassiou, M. 2006; 64 (5): 570-573


    Recently, the pyrazolopyrimidine, [11C] N,N-Diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide (DPA-713) has been reported as a new promising marker for the study of peripheral benzodiazepine receptors with positron emission tomography. In the present study, DPA-713 has been labelled from the corresponding nor-analogue using [11C]methyl triflate (CH3OTf). Conditions for HPLC were also modified to include physiological saline (aq. 0.9% NaCl)/ethanol:60/40 as mobile phase making it suitable for injection. The total time of radiosynthesis, including HPLC purification, was 18-20 min. This reported synthesis of [11C]DPA-713, using [11C]CH3OTf, resulted in an improved radiochemical yield (30-38%) compared to [11C]methyl iodide (CH3I) (9) with a simpler purification method. This ultimately enhances the potential of [11C]DPA-713 for further pharmacological and clinical evaluation. These improvements make this radioligand more suitable for automated synthesis which is of benefit where multi-dose preparations and repeated syntheses of radioligand are required.

    View details for DOI 10.1016/j.apradiso.2005.12.003

    View details for Web of Science ID 000237041800009

    View details for PubMedID 16427784

  • Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand BIOORGANIC & MEDICINAL CHEMISTRY James, M. L., Fulton, R. R., Henderson, D. J., Eberl, S., Melkle, S. R., Thomson, S., Allan, R. D., Dolle, F., Fulham, M. J., Kassiou, M. 2005; 13 (22): 6188-6194


    The novel pyrazolopyrimidine ligand, N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide 1 (DPA-713), has been reported as a potent ligand for the peripheral benzodiazepine receptor (PBR) displaying an affinity of K(i)=4.7 nM. In this study, 1 was successfully synthesised and demethylated to form the phenolic derivative 6 as precursor for labelling with carbon-11 (t(1/2) = 20.4 min). [11C]1 was prepared by O-alkylation of 6 with [11C]methyl iodide. The radiochemical yield of [(11)C]1 was 9% (non-decay corrected) with a specific activity of 36 GBq/micromol at the end of synthesis. The average time of synthesis including formulation was 13.2 min with a radiochemical purity >98%. In vivo assessment of [11C]1 was performed in a healthy Papio hamadryas baboon using positron emission tomography (PET). Following iv administration of [11C]1, significant accumulation was observed in the baboon brain and peripheral organs. In the brain, the radioactivity peaked at 20 min and remained constant for the duration of the imaging experiment. Pre-treatment with the PBR-specific ligand, PK 11195 (5 mg/kg), effectively reduced the binding of [11C]1 at 60 min by 70% in the whole brain, whereas pre-treatment with the central benzodiazepine receptor ligand, flumazenil (1mg/kg), had no inhibitory effect on [11C]1 uptake. These results indicate that accumulation of [11C]1 in the baboon represents selective binding to the PBR. These exceptional in vivo binding properties suggest that [11C]1 may be useful for imaging the PBR in disease states. Furthermore, [11C]1 represents the first ligand of its pharmacological class to be labelled for PET studies and therefore has the potential to generate new information on the pathological role of the PBR in vivo.

    View details for DOI 10.1016/j.bmc.2005.06.030

    View details for Web of Science ID 000232733000012

    View details for PubMedID 16039131