Molecular Imaging, vol. 16

2. Targeting HER2 in Nuclear Medicine for Imaging and Therapy

   Adriana V. F. Massicano, PhD¹, Bernadette V. Marquez-Nostra, PhD², Suzanne E. Lapi, PhD¹
   Molecular Imaging, vol. 17, First Published January 23, 2018.
   Abstract

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   Abstract

   Since its discovery, the human epidermal growth factor 2 (HER2) has been extensively studied. Presently, there are 2 standard diagnostic techniques to assess HER2 status in biopsies: immunohistochemistry and fluorescence in situ hybridization. While these techniques have played an important role in the treatment of patients with HER2-positive cancer, they both require invasive biopsies for analysis. Moreover, the expression of HER2 is heterogeneous in breast cancer and can change over the course of the disease. Thus, the degree of HER2 expression in the small sample size of biopsied tumors at the time of analysis may not represent the overall status of HER2 expression in the whole tumor and in between tumor foci in the metastatic setting as the disease progresses. Unlike biopsy, molecular imaging using probes against HER2 allows for a noninvasive, whole-body assessment of HER2 status in real time. This technique could potentially select patients who may benefit from HER2-directed therapy and offer alternative treatments to those who may not benefit. Several antibodies and small molecules against HER2 have been labeled with different radioisotopes for nuclear imaging and/or therapy. This review presents the most recent advances in HER2 targeting in nuclear medicine focusing on preclinical and clinical studies.
    
3. 

   Commentary to ¹⁸F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi: Imaging Activated Platelets in Clots—Are We Getting There?

   Andrew W. Stephens, MD, PhD¹, Norman Koglin, PhD¹, Ludger M. Dinkelborg, PhD¹
   Molecular Imaging, vol. 17, First Published January 19, 2018.
   Abstract

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   Abstract

   Thrombus formation can lead to heart attacks, stroke and pulmonary embolism, which are major causes of mortality. Current standard diagnostic imaging methods detect anatomic abnormalities such as vascular flow impairment but have limitations. By using a targeted molecular imaging approach critical components of a pathology can be selectively visualized and exploited for an improved diagnosis and patient management. The GPIIb/IIIa receptor is abundantly and specifically exposed on activated platelets and is the key receptor in thrombus formation. This commentary describes the current status of GPIIb/IIIa-based PET imaging approaches with a focus on the recently published preclinical data of the small-molecule PET tracer ¹⁸F-GP1. Areas of future research and potential clinical applications are discussed that may lead to an improved detection of critical thromboembolic events and an optimization of available antithrombotic therapies by tracking activated platelets.
    
4. 

   Reversible Electroporation–Mediated Liposomal Doxorubicin Delivery to Tumors Can Be Monitored With ⁸⁹Zr-Labeled Reporter Nanoparticles

   Govindarajan Srimathveeravalli, PhD¹², Dalya Abdel-Atti, BS¹, Carlos Pérez-Medina, PhD³, Haruyuki Takaki, MD, PhD⁴, Stephen B. Solomon, MD¹², Willem J. M. Mulder, PhD³⁵, Thomas Reiner, PhD¹²
   Molecular Imaging, vol. 17, First Published February 26, 2018.
   Abstract

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   Abstract

   Reversible electroporation (RE) can facilitate nanoparticle delivery to tumors through direct transfection and from changes in vascular permeability. We investigated a radiolabeled liposomal nanoparticle (⁸⁹Zr-NRep) for monitoring RE-mediated liposomal doxorubicin (DOX) delivery in mouse tumors. Intravenously delivered ⁸⁹Zr-NRep allowed positron emission tomography imaging of electroporation-mediated nanoparticle uptake. The relative order of ⁸⁹Zr-NRep injection and electroporation did not result in significantly different overall tumor uptake, suggesting direct transfection and vascular permeability can independently mediate deposition of ⁸⁹Zr-NRep in tumors. ⁸⁹Zr-NRep and DOX uptake correlated well in both electroporated and control tumors at all experimental time points. Electroporation accelerated ⁸⁹Zr-NRep and DOX deposition into tumors and increased DOX dosing. Reversible electroporation–related vascular effects seem to play an important role in nanoparticle delivery to tumors and drug uptake can be quantified with ⁸⁹Zr-NRep.
    
5. 

   Melanocortin 1 Receptor Targeted Imaging of Melanoma With Gold Nanocages and Positron Emission Tomography

   Yongfeng Zhao, PhD¹², Bo Pang, PhD³, Lisa Detering, MS¹, Hannah Luehmann, MS¹, Miaoxin Yang, PhD³, Kvar Black, PhD¹, Deborah Sultan, BS¹, Younan Xia,PhD³, Yongjian Liu, PhD¹
   Molecular Imaging, vol. 17, First Published June 6, 2018.
   Abstract

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   Abstract

   Purpose:

   Melanoma is a lethal skin cancer with unmet clinical needs for targeted imaging and therapy. Nanoscale materials conjugated with targeting components have shown great potential to improve tumor delivery efficiency while minimizing undesirable side effects in vivo. Herein, we proposed to develop targeted nanoparticles for melanoma theranostics.

   Method:

   In this work, gold nanocages (AuNCs) were conjugated with α-melanocyte-stimulating hormone (α-MSH) peptide and radiolabeled with ⁶⁴Cu for melanocortin 1 receptor-(MC1R) targeted positron emission tomography (PET) in a mouse B16/F10 melanoma model.

   Results:

   Their controlled synthesis and surface chemistry enabled well-defined structure and radiolabeling efficiency. In vivo pharmacokinetic evaluation demonstrated comparable organ distribution between the targeted and nontargeted AuNCs. However, micro-PET/computed tomography (CT) imaging demonstrated specific and improved tumor accumulation via MC1R-mediated delivery. By increasing the coverage density of α-MSH peptide on AuNCs, the tumor delivery efficiency was improved.

   Conclusion:

   The controlled synthesis, sensitive PET imaging, and optimal tumor targeting suggested the potential of targeted AuNCs for melanoma theranostics.
    
6. 

   PSMA Theranostics: Current Status and Future Directions

   Kambiz Rahbar, MD¹, Ali Afshar-Oromieh, MD², Hossein Jadvar, MD, PhD³, Hojjat Ahmadzadehfar, MD, MSc⁴
   Molecular Imaging, vol. 17, First Published June 6, 2018.
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   Abstract

   Prostate-specific membrane antigen (PSMA) is a promising target for imaging diagnostics and targeted radionuclide therapy (theranostics) of prostate cancer and its metastases. There is increasing evidence of encouraging response rates and a low toxicity profile of radioligand therapy (RLT) of metastatic castration-resistant prostate cancer using ¹⁷⁷Lu-labeled PSMA ligands. In this article, we review the current status of diagnostics and therapy using radiolabeled PSMA ligands. We also suggest protocols for patient selection criteria and conduct of PSMA-based RLT. Challenges and opportunities of PSMA theranostics are discussed.
    
7. 

   An Exploratory Study of Washout Rate Analysis for Thallium-201 Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging Using Cadmium Zinc Telluride Detectors

   Masaru Ishihara, MS¹², Masahisa Onoguchi, PhD², Takayuki Shibutani, PhD²
   Molecular Imaging, vol. 17, First Published June 28, 2018.
   Abstract

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   Abstract

   The aim of this study was to assess the washout rate (WOR) for thallium-201-chloride single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) using cadmium zinc telluride detectors for SPECT (CZT SPECT) versus conventional Anger-type SPECT (conventional SPECT). A total of 52 Japanese patients were examined using CZT SPECT and conventional SPECT, and the global WORs were compared. Additionally, the MPI WORs were compared for patients with a normal MPI versus those in whom MPI reflected the patients' multivessel disease (MVD) MPI. Washout rates were similar when approximated by CZT SPECT versus conventional SPECT 12.59 ± 2.26%/h vs 12.57 ± 2.27%/h (P = .997), respectively. The WOR values for CZT SPECT versus conventional SPECT were 13.42%/h (1.53%/h) vs 13.93%/h (1.24%/h) (P = .337), respectively, for 7 normal MPI patients, and 10.64 ± 2.20%/h vs 10.84 ± 2.26%/h (P = .848), respectively, for 7 MVD-MPI patients. The WOR values for normal MPI versus MVD-MPI patients for CZT SPECT were 13.42 ± 1.53%/h vs 10.64 ± 2.20%/h (P = .025), respectively. Thallium-201-chloride WOR values obtained with high-efficiency CZT SPECT, which enabled significantly reduced imaging times and use of a low-dose protocol, were similar to those obtained with conventional SPECT.
    
8. 

   Pharmacokinetic Evaluation of [¹¹C]CEP-32496 in Nude Mice Bearing BRAF^V600E Mutation-Induced Melanomas

   Cuiping Jiang, MMSc¹², Lin Xie, MD, PhD¹, Yiding Zhang, BSc¹, Masayuki Fujinaga, PhD¹, Wakana Mori, MSc¹, Yusuke Kurihara, PhD¹, Tomoteru Yamasaki, PhD¹,Feng Wang, MD, PhD², Ming-Rong Zhang, MD, PhD¹
   Molecular Imaging, vol. 17, First Published September 25, 2018.
   Abstract

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   Abstract

   CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAF^V600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([¹¹C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [¹¹C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAF^V600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [¹¹C]CEP-32496 showed high binding affinity for BRAF^V600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAF^V600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [¹¹C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [¹¹C]CEP-32496 in plasma. Our results indicate that [¹¹C]CEP-32496 has excellent specificity and affinity for the BRAF^V600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.
    
9. 

   The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils

   Lee Josephson, PhD¹², Nancy Stratman, MS³, YuTing Liu, MS⁴, Fang Qian, MS⁴, Steven H. Liang, PhD², Neil Vasdev, PhD¹², Shil Patel, PhD⁵
   Molecular Imaging, vol. 17, First Published September 14, 2018.
   Abstract

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   Abstract

   Development of an α-synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-binding compounds. [³H]BF-227 bound to α-Syn and amyloid β peptide (Aβ) fibrils with affinities (K_D) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as K_i) for α-Syn and Aβ fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the K_i(Aβ)/K_i(α-Syn) ratio, was 0.23 for BF-227. A similar or lower ratio was measured for analogues decorated with alkyl or oxyethylene chains attached to the oxygen at the 6 position of BF-227, suggesting a lack of involvement of the side chain in fibril binding. BF-227-like iodobenzoxazoles had lower affinities and poor α-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved α-Syn selectively having K_i(Aβ)/K_i(α-Syn) ranging from 2.2 to 5.1 with appreciable fibril affinity, although not sufficient to warrant further investigation. Compounds based on fluorobenzoxazoles might offer an approach to obtaining an α-Syn imaging agent with an appropriate affinity and selectivity.
    
10. 

    Adamantane/Cucurbituril: A Potential Pretargeted Imaging Strategy in Immuno-PET

    Martin G. Strebl, PhD¹, Jane Yang, BS¹, Lyle Isaacs, PhD², Jacob M. Hooker, PhD¹
    Molecular Imaging, vol. 17, First Published October 25, 2018.
    Abstract

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    Abstract

    Positron emission tomography (PET) imaging with biological macromolecules greatly expands the possibilities of molecular imaging. There are, however, practical aspects limiting the potential of the approach, including the dosimetric consequences of the slow kinetics of radiolabeled biomacromolecules. Pretargeting strategies have led to impactful improvements in the field but are themselves limited by shortcomings of available bioconjugation methodology. We report our initial findings concerning the suitability of the adamantane/cucurbit[7]uril system for pretargeted immuno-PET imaging and provide proof-of-concept PET/computed tomography imaging experiments to establish the stability and rapid formation of host–guest complexes in vivo. The adamantane/cucurbit[7]uril system itself without antibody conjugation has shown remarkably fast association kinetics and clearance in vivo. We further demonstrate the modulation of biodistribution achievable by cucurbituril complexation with relevance for pharmaceutical formulation as well as the radiosynthetic access to relevant reporter molecules labeled with ¹¹C or ¹⁸F. This work, an early proof-of-concept, supports the notion that the adamantane/cucurbit[7]uril system warrants further exploration in pretargeted PET imaging applications.
     
11. 

    Development and Characterization of an ¹⁸F-labeled Ghrelin Peptidomimetic for Imaging the Cardiac Growth Hormone Secretagogue Receptor

    Ahmed Abbas, MSc¹, Lihai Yu, PhD², Tyler Lalonde, BSc², Derek Wu, BSc³, Jonathan D. Thiessen, PhD¹⁴, Leonard G. Luyt, PhD²⁴⁵, Savita Dhanvantari, PhD¹³⁴⁶
    Molecular Imaging, vol. 17, First Published November 5, 2018.
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    Abstract

    One-third of patients with heart disease develop heart failure, which is diagnosed through imaging and detection of circulating biomarkers. Imaging strategies reveal morphologic and functional changes but fall short of detecting molecular abnormalities that can lead to heart failure, and circulating biomarkers are not cardiac specific. Thus, there is critical need for biomarkers that are endogenous to myocardial tissues. The cardiac growth hormone secretagogue receptor 1a (GHSR1a), which binds the hormone ghrelin, is a potential biomarker for heart failure. We have synthesized and characterized a novel ghrelin peptidomimetic tracer, an ¹⁸F-labeled analogue of G-7039, for positron emission tomography (PET) imaging of cardiac GHSR1a. In vitro analysis showed enhanced serum stability compared to natural ghrelin and significantly increased cellular uptake in GHSR1a-expressing OVCAR cells. Biodistribution studies in mice showed that tissue uptake of the tracer was independent of circulating ghrelin levels, and there was negligible cardiac uptake and high uptake in the liver, intestines, and kidneys. Specificity of tracer uptake was assessed using ghsr ^−/− mice; both static and dynamic PET imaging revealed no difference in cardiac uptake, and there was no significant correlation between cardiac standardized uptake values and GHSR1a expression. Our study lays the groundwork for further refinement of peptidomimetic PET tracers targeting cardiac GHSR1a.
     
12. 

    Scatter Artifact with Ga-68-PSMA-11 PET: Severity Reduced With Furosemide Diuresis and Improved Scatter Correction

    Courtney Lawhn-Heath, MD¹, Robert R. Flavell, MD, PhD¹, David E. Korenchan, PhD¹, Timothy Deller, MSEE², Spencer Lake, MD¹, Peter R. Carroll, MD, MPH³,Thomas A. Hope, MD¹⁴
    Molecular Imaging, vol. 17, First Published December 3, 2018.
    Abstract

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    Abstract

    Purpose:

    To assess the utility of furosemide diuresis and the role of an improved scatter correction algorithm in reducing scatter artifact severity on Ga-68- Prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET).

    Materials and Methods:

    A total of 139 patients underwent Ga-68-PSMA-11 PET imaging for prostate cancer: 47 non-time-of-flight (non-TOF) PET/computed tomography, 51 PET/magnetic resonance imaging (MRI) using the standard TOF scatter correction algorithm, and 41 PET/MRI using an improved TOF scatter correction algorithm. Whole-body PET acquisitions were subdivided into 3 regions: around kidneys; between kidneys and bladder; and around bladder. The images were reviewed, and scatter artifact severity was rated using a Likert-type scale.

    Results:

    The worst scatter occurred when using non-TOF scatter correction without furosemide, where 42.1% of patients demonstrated severe scatter artifacts in 1 or more regions. Improved TOF scatter correction resulted in the smallest percentage of studies with severe scatter (6.5%). Scatter ratings by region were lowest using improved TOF scatter correction. Furosemide reduced mean scatter severity when using non-TOF and standard TOF.

    Conclusions:

    Both furosemide and scatter correction algorithm play a role in reducing scatter in PSMA PET. Improved TOF scatter correction resulted in the lowest scatter severity.
     
13. 

    Preclinical Evaluation of ¹⁸F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors

    Emre Demirci, MD¹², Rafay Ahmed, MD¹, Meltem Ocak, PhD¹³, Joseph Latoche, BS¹, April Radelet, BS¹, Nicole DeBlasio, BS¹, N. Scott Mason, PhD¹, Carolyn J. Anderson, PhD¹⁴⁵⁶, James M. Mountz, MD, PhD¹
    Molecular Imaging, vol. 16, First Published January 10, 2017.
    Abstract

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    Abstract

    Purpose:

    We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (¹⁸F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model.

    Procedures:

    BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal ¹⁸F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, ¹⁸F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment.

    Results:

    Treated mice demonstrated increased ¹⁸F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline (P > .05); however, T/L ratios of the treatment group showed significant ¹⁸F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment (P < .05), but no significant difference at 1 day posttreatment.

    Conclusion:

    2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.
     
14. 

    Multimodal Imaging of Patients With Gliomas Confirms ¹¹C-MET PET as a Complementary Marker to MRI for Noninvasive Tumor Grading and Intraindividual Follow-Up After Therapy

    Kai R. Laukamp, MD¹², Florian Lindemann, PhD³, Matthias Weckesser, MD⁴, Volker Hesselmann, MD⁵, Sandra Ligges, PhD⁶, Johannes Wölfer, MD⁷, Astrid Jeibmann, MD⁸, Bastian Zinnhardt, PhD¹, Thomas Viel, PhD¹, Michael Schäfers, MD¹⁴⁹, Werner Paulus, MD⁸⁹, Walter Stummer, MD⁷⁹, Otmar Schober, PhD, MD¹⁴⁹,Andreas H. Jacobs, MD¹⁴⁹¹⁰
    Molecular Imaging, vol. 16, First Published January 24, 2017.
    Abstract

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    Abstract

    The value of combined L-(methyl-[¹¹C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n = 65 patients with histologically verified brain lesions n = 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software "visualization and analysis framework volume rendering engine (Voreen)" was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined by MET-PET (21.6 ± 36.8 cm³), T1w-Gd-MRI (3.9 ± 7.8 cm³), and FLAIR/T2-MRI (64.8 ± 60.4 cm³; P < .001). The MET-PET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8 ± 35.0 cm³ and without changes in FLAIR/T2 10.3 ± 25.7 cm³. FLAIR/T2-MRI visualized greatest tumor extent with differences to MET-PET being greater in posttherapy (64.6 ± 62.7 cm³) than in newly diagnosed patients (20.5 ± 52.6 cm³). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n = 10 from other gliomas n = 16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management.
     
15. 

    Image-Based Analysis of Tumor Localization After Intra-Arterial Delivery of Technetium-99m-Labeled SPIO Using SPECT/CT and MRI

    In Joon Lee, MD, PhD¹, Ji Yong Park, MS²³, Young-il Kim, MD, PhD²⁴, Yun-Sang Lee, PhD²⁴, Jae Min Jeong, PhD², Jaeil Kim, BS², Euishin Edmund Kim, MD, PhD⁴⁵,Keon Wook Kang, MD, PhD², Dong Soo Lee, MD, PhD²⁴, Seonji Jeong, MD⁶, Eun Jeong Kim, BS⁶, Young Il Kim, MD, PhD⁶⁷, Jin Wook Chung, MD, PhD⁶
    Molecular Imaging, vol. 16, First Published January 24, 2017.
    Abstract

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    Abstract

    The aim of this study is to evaluate the localization of ^99mTc-labeled dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles to the liver tumor using image-based analysis. We delivered ^99mTc-SPIO intravenously or intra-arterially (IA) with/without Lipiodol to compare the tumor localization by gamma scintigraphy, single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) in a rabbit liver tumor. The gamma and SPECT image-based analysis shows that the uptake ratio of the tumor to the normal liver parenchyma is highest after delivery of ^99mTc-SPIO with Lipiodol IA and that well correlates with the trend of the signal decrease in the liver MRIs. Intra-arterial delivery of SPIO with Lipiodol might be a good drug delivery system targeting the hepatic tumors, as confirmed by image-based analysis.
     
16. 

    PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury

    Hui Liu, PhD, MD¹, Hongjun Jin, PhD¹, Xuyi Yue, PhD¹, Junbin Han, PhD¹, Pamela Baum, SRS², Dana R. Abendschein, PhD², Zhude Tu, PhD¹
    Molecular Imaging, vol. 16, First Published January 30, 2017.
    Abstract

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    Abstract

    Sphingosine-1-phosphate receptor (S1PR) activation plays a key role in vascular inflammatory response. Here, we report in vivo validation of [¹¹C]TZ3321, a potent S1PR1 radioligand, for imaging vascular inflammation in a rat model of carotid injury. The right common carotid artery of male adult Sprague-Dawley rats was injured by balloon overinflation that denuded the endothelium and distended the vessel wall. Animals received a 60-minute micro-positron emission tomography (micro PET) scan with [¹¹C]TZ3321 at 72 hours after injury. Ex vivo autoradiography was also conducted. The expression and cellular location of S1PR1 were examined by immunohistological analysis. Three-dimensional (3D) reconstruction of the first 100-second microPET/computed tomography (CT) image indicated the location of bilateral common carotid arteries. [¹¹C]TZ3321 displayed significantly higher accumulation (standardized uptake values: 0.93 ± 0.07 vs 0.78 ± 0.09, n = 6, P = .001) in the injured carotid artery than in the contralateral side. Increased tracer uptake in the injured artery was confirmed by autoradiography (photostimulated luminescence measures: 85.5 ± 0.93 vs 71.48 ± 6.22, n = 2). Concordantly, high S1PR1expression was observed in infiltrated inflammatory cells in the injured artery. Our studies demonstrate [¹¹C]TZ3321 microPET is able to detect the acute upregulation of S1PR1 expression in inflamed carotid artery. Therefore, [¹¹C]TZ3321 has potential to be a PET radiotracer for detecting early inflammatory response and monitoring therapeutic efficacy of vascular inflammation.
     
17. 

    Preclinical Multimodal Molecular Imaging Using ¹⁸F-FDG PET/CT and MRI in a Phase I Study of a Knee Osteoarthritis in In Vivo Canine Model

    Maria I. Menendez, DVM, PhD¹, Bianca Hettlich, DrMedVet¹², Lai Wei, PhD³, Michael V. Knopp, MD, PhD¹
    Molecular Imaging, vol. 16, First Published March 24, 2017.
    Abstract

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    Abstract

    The aim of this study was to use a multimodal molecular imaging approach to serially assess regional metabolic changes in the knee in an in vivo anterior cruciate ligament transection (ACLT) canine model of osteoarthritis (OA). Five canine underwent ACLT in one knee and the contralateral knee served as uninjured control. Prior, 3, 6, and 12 weeks post-ACLT, the dogs underwent ¹⁸F-fluoro-d-glucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The MRI was coregistered with the PET/CT, and 3-dimensional regions of interest (ROIs) were traced manually and maximum standardized uptake values (SUV_max) were evaluated. ¹⁸F-fluoro-d-glucose SUV_max in the ACLT knee ROIs was significantly higher compared to the uninjured contralateral knees at 3, 6, and 12 weeks. Higher ¹⁸F-FDG uptake observed in ACLT knees compared to the uninjured knees reflects greater metabolic changes in the injured knees over time. Knee ¹⁸F-FDG uptake in an in vivo ACLT canine model using combined PET/CT and MRI demonstrated to be highly sensitive in the detection of metabolic alterations in osseous and nonosteochondral structures comprising the knee joint. ¹⁸F-fluoro-d-glucose appeared to be a capable potential imaging biomarker for early human knee OA diagnosis, prognosis, and management.
     
18. 

    Brain and Brown Adipose Tissue Metabolism in Transgenic Tg2576 Mice Models of Alzheimer Disease Assessed Using ¹⁸F-FDG PET Imaging

    Robert A. Coleman, PhD¹, Christopher Liang, BS¹, Rima Patel, BS¹, Sarah Ali, BS¹, Jogeshwar Mukherjee, PhD¹
    Molecular Imaging, vol. 16, First Published May 2, 2017.
    Abstract

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    Abstract

    Objective:

    Imaging animal models of Alzheimer disease (AD) is useful for the development of therapeutic drugs and understanding AD. Transgenic Swedish hAPPswe Tg2576 mice are a good model of β-amyloid plaques. We report ¹⁸F-fluoro-2-deoxyglucose (¹⁸F-FDG) positron emission tomography (PET) imaging of brain and intrascapular brown adipose tissue (IBAT) in transgenic mice 2576 (Tg2576) and wild-type (WT) mice.

    Methods:

    Transgenic Tg2576 mice and WT mice, >18 months were injected intraperitonally with ≈ 25 to 30 MBq ¹⁸F-FDG while awake. After 60 minutes, they were anesthetized with isoflurane (2.5%) and imaged with Inveon MicroPET. Select mice were killed, imaged ex vivo, and 20 µm sections cut for autoradiography. ¹⁸F-FDG uptake in brain and IBAT PET and brain autoradiographs were analyzed.

    Results:

    Fasting blood glucose levels averaged 120 mg/dL for WT and 100 mg/dL for Tg2576. Compared to WT, Tg2576 mice exhibited a decrease in SUVglc in the various brain regions. Average reductions in the cerebrum regions were as high as −20%, while changes in cerebellum were −3%. Uptake of ¹⁸F-FDG in IBAT decreased by −60% in Tg2576 mice and was found to be significant. Intrascapular brown adipose tissue findings in Tg2576 mice are new and not previously reported. Use of blood glucose for PET data analysis and corpus callosum as reference region for autoradiographic analysis were important to detect change in Tg2576 mice.

    Conclusion:

    Our results suggest that ¹⁸F-FDG uptake in the Tg2576 mice brain show ¹⁸F-FDG deficits only when blood glucose is taken into consideration.
     
19. 

    Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

    Hongyoon Choi, MD, PhD¹, Jeong Hee Han, PhD¹, Sue Yeon Lim, MS¹, Inki Lee, MD¹, Young-Seok Cho, MD, PhD², Eun Ju Chun, MD, PhD³, Won Woo Lee, MD, PhD¹⁴
    Molecular Imaging, vol. 16, First Published April 23, 2017.
    Abstract

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    Abstract

    Positron emission tomography (PET)/computed tomography (CT) using sodium [¹⁸F]fluoride (Na[¹⁸F]F) has been proven to be a promising hot-spot imaging modality for myocardial infarction (MI). We investigated Na[¹⁸F]F uptake in ischemia–reperfusion injury (IRI) of rats and humans. Sodium [¹⁸F]fluoride PET/CT was performed in Sprague-Dawley rats that had IRI surgery, and it readily demonstrated prominent Na[¹⁸F]F uptake in the infarct area post-IRI. Sodium [¹⁸F]fluoride uptake was matched with negative 2,3,5-triphenyl-2H-tetrazolium chloride staining results, accompanied by myocardial apoptosis and associated with positive calcium staining results. Furthermore, area at risk was negative for Na[¹⁸F]F uptake. Cyclosporine A (CysA) treatment reduced standardized uptake value of ¹⁸F over the infarct area, and a significant decrease in infarct size was also observed by the CysA treatment. In humans, Na[¹⁸F]F PET/CT readily demonstrated increased Na[¹⁸F]F uptake in the 2 patients with MI post-percutaneous coronary intervention. In conclusion, this study sheds light on the potential utility of Na[¹⁸F]F PET/CT as a hot-spot imaging modality for myocardial IRI.
     
20. 

    Fluorescent, Plasmonic, and Radiotherapeutic Properties of the ¹⁷⁷Lu–Dendrimer-AuNP–Folate–Bombesin Nanoprobe Located Inside Cancer Cells

    Héctor Mendoza-Nava, PhD¹², Guillermina Ferro-Flores, PhD¹, Flor de María Ramírez, PhD³, Blanca Ocampo-García, PhD¹, Clara Santos-Cuevas, PhD¹, Erika Azorín-Vega, PhD¹, Nallely Jiménez-Mancilla, PhD⁴, Myrna Luna-Gutiérrez, PhD¹, Keila Isaac-Olivé, PhD²
    Molecular Imaging, vol. 16, First Published May 4, 2017.
    Abstract

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    Abstract

    The integration of fluorescence and plasmonic properties into one molecule is of importance in developing multifunctional imaging and therapy nanoprobes. The aim of this research was to evaluate the fluorescent properties and the plasmonic–photothermal, therapeutic, and radiotherapeutic potential of ¹⁷⁷Lu–dendrimer conjugated to folate and bombesin with gold nanoparticles in the dendritic cavity (¹⁷⁷Lu–DenAuNP–folate–bombesin) when it is internalized in T47D breast cancer cells. The intense near-Infrared (NIR) fluorescence emitted at 825 nm from the conjugate inside cells corroborated the usefulness of DenAuNP–folate–bombesin for optical imaging. After laser irradiation, the presence of the nanosystem in cells caused a significant increase in the temperature of the medium (46.8°C, compared to 39.1°C without DenAuNP–folate–bombesin, P < 0.05), resulting in a significant decrease in cell viability (down to 16.51% ± 1.52%) due to the ¹⁷⁷Lu–DenAuNP–folate–bombesin plasmonic properties. After treatment with ¹⁷⁷Lu–DenAuNP–folate–bombesin, the T47D cell viability decreased 90% because of the radiation-absorbed dose (63.16 ± 4.20 Gy) delivered inside the cells. The ¹⁷⁷Lu–DenAuNP–folate–bombesin nanoprobe internalized in cancer cells exhibited properties suitable for optical imaging, plasmonic–photothermal therapy, and targeted radiotherapy.
     
21. 

    Dual-Energy SPECT and the Development of Peptide p5+14 for Imaging Amyloidosis

    Jonathan S. Wall, PhD¹, Stephen J. Kennel, PhD¹, Emily B. Martin, PhD¹
    Molecular Imaging, vol. 16, First Published May 11, 2017.
    Abstract

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    Abstract

    Amyloidosis is associated with a number of rare diseases and is characterized by the deposition, in abdominothoracic organs and peripheral nerves, of extracellular protein fibrils, which leads to dysfunction and severe morbidity. Effective clinical evaluation and management of patients with systemic amyloidosis are hampered by the lack of a noninvasive, quantitative method for detecting whole-body amyloid load. We have used a battery of assays including dual-energy SPECT imaging and comparative effectiveness studies in support of translation of a synthetic polybasic peptide, p5+14, as a novel radiotracer for visualization of amyloidosis by molecular imaging. These data provide support for a phase 1 positron emission tomography/computed tomography imaging trial of this reagent, labeled with iodine-124, in patients with all forms of systemic amyloidosis.