bluuebunny/crossref_metadata_2025 huggingface dataset:
111In-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment
Authors: Gaykema Sietske B.M. , de Jong Johan R. , Perik Patrick J. , Brouwers Adrienne H. , Schröder Carolien P. , Munnink Thijs H. Oude , Bongaerts Alphons H.H. , de Vries Elisabeth G.E. , Hooge Marjolijn N. Lub-de
Published: March 2018

Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab treatment on 111In-trastuzumab uptake. Patients received trastuzumab weekly and paclitaxel once every 3 weeks. 111In-trastuzumab was injected on day 1 of cycle 1 and day 15 of cycle 4. Whole-body planar scintigraphy was acquired at different time points postinjection. Tumor uptake and organ distribution between the first and repeated scan series were calculated via residence times. Twenty-five tumor lesions in 12 patients were visualized on both scintigraphy series. Tumor uptake decreased (19.6%; p = .03). The residence times of normal organs remained similar except for the cardiac blood pool (+ 16.3%; p = .014). Trastuzumab treatment decreases tumor 111In-trastuzumab uptake around 20%. HER2 imaging is feasible during trastuzumab treatment.
Magnetic Resonance Imaging Visualization of Vulnerable Atherosclerotic Plaques at the Brachiocephalic Artery of Apolipoprotein E Knockout Mice by the Blood-Pool Contrast Agent B22956/1
Authors: Parolini Cinzia , Busnelli Marco , Ganzetti Giulia S. , Dellera Federica , Manzini Stefano , Scanziani Eugenio , Johnson Jason L. , Sirtori Cesare R. , Chiesa Giulia
Published: March 2018

The aim of this study was to identify, by magnetic resonance imaging (MRI), the ability of the blood-pool contrast agent B22956/1 to detect atherosclerotic plaques developing at the brachiocephalic artery of apolipoprotein E knockout (apoE-KO) mice and to possibly identify vulnerable atherosclerotic lesions. After high-fat feeding for 8 or 12 weeks, MRIs of brachiocephalic arteries were acquired before and after B22956/1 administration; then vessels were removed and analyzed by histology. B22956/1 injection caused a rapid increase in plaque signal enhancement and plaque to muscle contrast values, which remained stable up to 70 minutes. A linear correlation between signal enhancement and macrophage content was found 10 minutes after B22956/1 injection ( p < .01). Signal enhancement and plaque to muscle contrast values correlated with macrophage content 40 minutes after contrast agent administration ( p < .01). Finally, 70 minutes after B22956/1 infusion, plaque to muscle contrast significantly correlated with the percentage of stenosis ( p < .005). B22956/1 administration to high fat-fed apoE-KO mice resulted in a rapid enhancement of atherosclerotic plaques and in a great ability to rapidly visualize vulnerable plaques, characterized by a high macrophage content. These results suggest that B22956/1 could represent an interesting tool for the identification of atherosclerotic plaques potentially leading to acute cardiovascular events.
Continuous Flushing of the Bladder in Rodents Reduces Artifacts and Improves Quantification in Molecular Imaging
Authors: Deleye Steven , Heylen Marthe , Deiteren Annemie , De Man Joris , Stroobants Sigrid , De Winter Benedicte , Staelens Steven
Published: March 2018

In this study, we evaluated the partial volume effect (PVE) of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) tracer accumulation in the bladder on the positron emission tomographic (PET) image quantification in mice and rats suffering from inflammatory bowel disease. To improve the accuracy, we implemented continuous bladder flushing procedures. Female mice and rats were scanned using microPET/computed tomography (CT) at baseline and after induction of acute colitis by injecting 2,4,6-trinitrobenzene sulfonic acid (TNBS) intrarectally. During the scans, the bladder was continuously flushed in one group, whereas in the other group, no bladder flushing was performed. As a means of in vivo and ex vivo validation of the inflammation, animals also underwent colonoscopy and were sacrificed for gamma counting (subpopulation) and to score the colonic damage both micro- and macroscopically as well as biochemically. At baseline, the microPET signal in the colon of both mice and rats was significantly higher in the nonflushed group compared to the flushed group, caused by the PVE of tracer activity in the bladder. Hence, the colonoscopy and postmortem analyses showed no significant differences at baseline between the flushed and nonflushed animals. TNBS induced significant colonic inflammation, as revealed by colonoscopic and postmortem scores, which was not detected by microPET in the mice without bladder flushing, again because of spillover of bladder activity in the colonic area. MicroPET in bladder-flushed animals did reveal a significant increase in 18F-FDG uptake. Correlations between microPET and colonoscopy, macroscopy, microscopy, and myeloperoxidase yielded higher Spearman rho values in mice with continuously flushed bladders during imaging. Comparable, although somewhat less pronounced, results were shown in the rat. Continuous bladder flushing reduced image artifacts and is mandatory for accurate image quantification in the pelvic region for both mice and rats. We designed and validated experimental protocols to facilitate such.
Comparison of Amino Acid Positron Emission Tomographic Radiotracers for Molecular Imaging of Primary and Metastatic Brain Tumors
Authors: Juhász Csaba , Dwivedi Shalini , Kamson David O. , Michelhaugh Sharon K. , Mittal Sandeep
Published: March 2018

Positron emission tomography (PET) is an imaging technology that can detect and characterize tumors based on their molecular and biochemical properties, such as altered glucose, nucleoside, or amino acid metabolism. PET plays a significant role in the diagnosis, prognostication, and treatment of various cancers, including brain tumors. In this article, we compare uptake mechanisms and the clinical performance of the amino acid PET radiotracers (L-[methyl-11C]methionine [MET], 18F-fluoroethyl-tyrosine [FET], 18F-fluoro-L- dihydroxy-phenylalanine [FDOPA], and 11C-alpha-methyl-L-tryptophan [AMT]) most commonly used for brain tumor imaging. First, we discuss and compare the mechanisms of tumoral transport and accumulation, the basis of differential performance of these radioligands in clinical studies. Then we summarize studies that provided direct comparisons among these amino acid tracers and to clinically used 2-deoxy-2[18F]fluoro-D-glucose [FDG] PET imaging. We also discuss how tracer kinetic analysis can enhance the clinical information obtained from amino acid PET images. We discuss both similarities and differences in potential clinical value for each radioligand. This comparative review can guide which radiotracer to favor in future clinical trials aimed at defining the role of these molecular imaging modalities in the clinical management of brain tumor patients.
Manganese-Enhanced Magnetic Resonance Imaging for Early Detection and Characterization of Breast Cancers
Authors: Alhamami Mosa , Mokhtari Reza Bayat , Ganesh Tameshwar , Nofiele Joris Tchouala , Yeger Herman , Cheng Hai-Ling Margaret
Published: March 2018

Very early cancer detection is the key to improving cure. Our objective was to investigate manganese (Mn)-enhanced magnetic resonance imaging (MRI) for very early detection and characterization of breast cancers. Eighteen NOD scid gamma mice were inoculated with MCF7, MDA, and LM2 breast cancer cells and imaged periodically on a 3 T scanner beginning on day 6. T1-weighted imaging and T1 measurements were performed before and 24 hours after administering MnCl2. At the last imaging session, Gd-DTPA was administered and tumors were excised for histology (hematoxylin-eosin and CD34 staining). All mice, except for two inoculated with MCF7 cells, developed tumors. Tumors enhanced uniformly on Mn and showed clear borders. Early small tumors (# 5 mm3) demonstrated the greatest enhancement with a relative R1 (1/T1) change of 1.57 ± 0.13. R1 increases correlated with tumor size ( r = −.34, p − .04). Differences in R1 increases among the three tumor subtypes were most evident in early tumors. Histology confirmed uniform cancer cell distribution within tumor masses and vasculature in the periphery, which was consistent with rim-like enhancement on Gd-DTPA. Mn-enhanced MRI is a promising approach for detecting very small breast cancers in vivo and may be valuable for very early cancer detection.
Construction and Radiolabeling of Adenovirus Variants that Incorporate Human Metallothionein into Protein IX for Analysis of Biodistribution
Authors: Liu Lei , Rogers Buck E. , Aladyshkina Natalia , Cheng Bing , Lokitz Stephen J. , Curiel David T. , Mathis J. Michael
Published: March 2018

Using adenovirus (Ad)-based vectors is a promising strategy for novel cancer treatments; however, current tracking approaches in vivo are limited. The C-terminus of the Ad minor capsid protein IX (pIX) can incorporate heterologous reporters to monitor biodistribution. We incorporated metallothionein (MT), a low-molecular-weight metal-binding protein, as a fusion to pIX. We previously demonstrated 99mTc binding in vitro to a pIX-MT fusion on the Ad capsid. We investigated different fusions of MT within pIX to optimize functional display. We identified a dimeric MT construct fused to pIX that showed significantly increased radiolabeling capacity. After Ad radiolabeling, we characterized metal binding in vitro. We explored biodistribution in vivo in control mice, mice pretreated with warfarin, mice preimmunized with wild-type Ad, and mice that received both warfarin pretreatment and Ad preimmunization. Localization of activity to liver and bladder was seen, with activity detected in spleen, intestine, and kidneys. Afterwards, the mice were euthanized and selected organs were dissected for further analysis. Similar to the imaging results, most of the radioactivity was found in the liver, spleen, kidneys, and bladder, with significant differences between the groups observed in the liver. These results demonstrate this platform application for following Ad dissemination in vivo.
In Vivo Bioluminescence Imaging of Transplanted Mesenchymal Stem Cells as a Potential Source for Pancreatic Regeneration
Authors: Lee Song , Youn Hyewon , Chung Taemoon , Hwang Do Won , Oh So Won , Kang Keon Wook , Chung June-Key , Lee Dong Soo
Published: March 2018

Stem cell therapy has been studied intensively as a promising therapeutic strategy toward a cure for diabetes. To study the effect of mesenchymal stem cell (MSC) transplantation for pancreatic regeneration, we monitored the localization and distribution of transplanted MSCs by bioluminescence imaging in a mouse model. Bone marrow MSCs were isolated and transfected with a highly sensitive firefly luciferase reporter gene. To assess the efficiency of MSC transplantation, a partially pancreatectomized (PPx) mouse model was used. Transplanted MSCs were monitored by confocal microscopy and in vivo bioluminescence imaging. Daily blood glucose levels and glucose tolerance were measured. Insulin-secreting beta cells were immunostained, and insulin levels were measured via enzyme-linked immunosorbent assay. Bioluminescence signals were clearly detected from the transplanted MSCs in the pancreatic region regardless of injection route. However, locally injected MSCs exhibited more rapid proliferation than ductally injected MSCs. PPx mice harboring transplanted MSCs gradually recovered from impaired glucose tolerance. Although insulin secretion was not observed in MSCs, transplanted MSCs facilitate the injured pancreas to recover its function. In vivo optical imaging of transplanted MSCs using a highly sensitive luciferase reporter enables the assessment of MSC transplantation efficiency in a PPx mouse model.
Combination of Single-Photon Emission Computed Tomography and Magnetic Resonance Imaging to Track 111In-Oxine–Labeled Human Mesenchymal Stem Cells in Neuroblastoma-Bearing Mice
Authors: Cussó Lorena , Mirones Isabel , Peña-Zalbidea Santiago , García-Vázquez Verónica , García-Castro Javier , Desco Manuel
Published: March 2018

Homing is an inherent, complex, multistep process performed by cells such as human bone marrow mesenchymal stem cells (hMSCs) to travel from a distant location to inflamed or damaged tissue and tumors. This ability of hMSCs has been exploited as a tumortargeting strategy in cell-based cancer therapy. The purpose of this study was to investigate the applicability of 111In-oxine for tracking hMSCs in vivo by combining single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). 111In-labeled hMSCs (106 cells) were infused intraperitoneally in neuroblastoma-bearing mice, whereas a control group received a dose of free 111In-oxine. SPECT and MRI studies were performed 24 and 48 hours afterwards. Initially, the images showed similar activity in the abdomen in both controls and hMSC-injected animals. In general, abdominal activity decreases at 48 hours. hMSC-injected animals showed increased uptake in the tumor area at 48 hours, whereas the control group showed a low level of activity at 24 hours, which decreased at 48 hours. In conclusion, tracking 111In-labeled hMSCs combining SPECT and MRI is feasible and may be transferable to clinical research. The multimodal combination is essential to ensure appropriate interpretation of the images.
Position for Site-Specific Attachment of a DOTA Chelator to Synthetic Affibody Molecules Has a Different Influence on the Targeting Properties of 68Ga-Compared to 111In-Labeled Conjugates
Authors: Honarvar Hadis , Strand Joanna , Perols Anna , Orlova Anna , Selvaraju Ram Kumar , Karlström Amelie Eriksson , Tolmachev Vladimir
Published: March 2018

Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1 which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.
In Vivo Monitoring of Parathyroid Hormone Treatment after Myocardial Infarction in Mice with [68Ga]Annexin A5 and [18F]Fluorodeoxyglucose Positron Emission Tomography
Authors: Lehner Sebastian , Todica Andrei , Vanchev Yordan , Uebleis Christopher , Wang Hao , Herrler Tanja , Wängler Carmen , Cumming Paul , Böning Guido , Franz Wolfgang M. , Bartenstein Peter , Hacker Marcus , Brunner Stefan
Published: March 2018

[68Ga]Annexin A5 positron emission tomography (PET) reveals the externalization of phosphatidylserine as a surrogate marker for apoptosis. We tested this technique for therapy monitoring in a murine model of myocardial infarction (MI) including parathyroid hormone (PTH) treatment. MI was induced in mice, and they were assigned to the saline or the PTH group. On day 2, they received [68Ga]annexin A5 PET or histofluorescence TUNEL staining. Mice had 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET examinations on days 6 and 30 for calculation of the left ventricular ejection fraction and infarct area. [68Ga]Annexin A5 uptake was 7.4 ± 1.3 %ID/g within the infarction for the controls and 4.5 ± 1.9 %ID/g for the PTH group ( p = .013). TUNEL staining revealed significantly more apoptotic cells in the infarct area on day 2 in the controls (64 ± 9%) compared to the treatment group (52 ± 4%; p = .045). FDG-PET revealed a significant decrease in infarct size in the treatment group and an increase in the controls. Examinations of left ventricular ejection fraction on days 6 and 30 did not reveal treatment effects. [68Ga]Annexin A5 PET can detect the effects of PTH treatment as a marker of apoptosis 2 days after MI; ex vivo examination confirmed significant rescue of myocardiocytes. FDG-PET showed a small but significant reduction in infarct size but no functional improvement.
In vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse
Authors: Lee Eun Seong , Im Hyung-Jun , Kim Han Soo , Youn Hyewon , Lee Hong J. , Kim Seung U. , Hwang Do Won , Lee Dong Soo
Published: March 2018

We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc) were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%), and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%). In the mice with initial lung signals (4 of 9, 44.4%), the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally.
Dual in vivo Photoacoustic and Fluorescence Imaging of HER2 Expression in Breast Tumors for Diagnosis, Margin Assessment, and Surgical Guidance
Authors: Maeda Azusa , Bu Jiachuan , Chen Juan , Zheng Gang , DaCosta Ralph S.
Published: March 2018

Biomarker-specific imaging probes offer ways to improve molecular diagnosis, intraoperative margin assessment, and tumor resection. Fluorescence and photoacoustic imaging probes are of particular interest for clinical applications because the combination enables deeper tissue penetration for tumor detection while maintaining imaging sensitivity compared to a single optical imaging modality. Here we describe the development of a human epidermal growth factor receptor 2 (HER2)-targeting imaging probe to visualize differential levels of HER2 expression in a breast cancer model. Specifically, we labeled trastuzumab with Black Hole Quencher 3 (BHQ3) and fluorescein for photoacoustic and fluorescence imaging of HER2 overexpression, respectively. The dual-labeled trastuzumab was tested for its ability to detect HER2 overexpression in vitro and in vivo. We demonstrated an over twofold increase in the signal intensity for HER2-overexpressing tumors in vivo, compared to low–HER2-expressing tumors, using photoacoustic imaging. Furthermore, we demonstrated the feasibility of detecting tumors and positive surgical margins by fluorescence imaging. These results suggest that multimodal HER2-specific imaging of breast cancer using the BHQ3-fluorescein trastuzumab enables molecular-level detection and surgical margin assessment of breast tumors in vivo. This technique may have future clinical impact for primary lesion detection, as well as intraoperative molecular-level surgical guidance in breast cancer.
[13N]Ammonia Positron Emission Tomographic/Computed Tomographic Imaging Targeting Glutamine Synthetase Expression in Prostate Cancer
Authors: Shi Xinchong , Zhang Xiangsong , Yi Chang , Liu Yubo , He Qiao
Published: March 2018

The purpose of this study was to investigate the expression of glutamine synthetase (GS) in prostate cancer (PCa) and the utility of [13N]ammonia positron emission tomography/computed tomography (PET/CT) in the imaging of PCa. The uptake ratio of [13N]ammonia and the expression of GS in PC3 and DU145 cells was measured. Thirty-four patients with suspected PCa underwent [13N]ammonia PET/CT imaging, and immunohistochemistry staining of GS was performed. The uptake of [13N]ammonia in PC3 and DU145 cells elevated along with the decrease in glutamine in medium. The expression of GS messenger ribonucleic acid and protein also increased when glutamine was deprived. In biopsy samples, the GS expression scores were significantly higher in PCa tissue than in benign tissues ( p < .001), and there was a positive correlation between the maximum GS expression scores and Gleason scores (Spearman r = .52). In 34 patients, [13N]ammonia uptake in PCa segments was significantly higher than that in benign segments ( p ≤ .01), and there was a weak correlation between GS expression scores and the uptake of [13N]ammonia (Spearman r = .47). The expression of GS in PCa cells upregulated along with the deprivation of glutamine. GS is the main reason for the uptake of [13N]ammonia, and [13N]ammonia is a useful tracer for PCa imaging.
Preclinical Validation of 99mTc–Annexin A5–128 in Experimental Autoimmune Myocarditis and Infective Endocarditis: Comparison with 99mTc–HYNIC–Annexin A5
Authors: Benali Khadija , Louedec Liliane , Azzouna Rana Ben , Merceron Olivier , Nassar Pierre , Al Shoukr Faisal , Petiet Anne , Barbato Donato , Michel Jean-Baptiste , Sarda-Mantel Laure , Le Guludec Dominique , Rouzet Francois
Published: March 2018

Hydrazinonicotinamide–annexin A5 (HYNIC-Anx), a 99m technetium (99mTc)-labeled agent targeting phosphatidylserine, proved to be sensitive for the detection of apoptosis and thrombosis but is no longer available for clinical use. A mutant of human annexin designed for direct 99mTc labeling (referred to as Anx A5–128) showed improved binding affinity to phosphatidylserine and is expected to be used in humans. We compared both radiotracers with regard to pharmacokinetics and diagnostic ability in animal models. Biodistribution studies were performed in normal rats. Radiolabeled Anx A5–128 and HYNIC-Anx were compared in cardiovascular settings involving phosphatidylserine expression: experimental autoimmune myocarditis and infective endocarditis. Initial blood clearance was faster for Anx A5–128 than for HYNIC-Anx, and tissue biodistribution was similar overall for both tracers. The diagnostic sensitivity of Anx A5–128 was excellent and comparable to that of HYNIC-Anx. Anx A5–128 showed biodistribution and diagnostic ability similar to those of the HYNIC-Anx derivative, supporting its translation to clinical use.
Relationship between Apoptosis Imaging and Radioiodine Therapy in Tumor Cells with Different Sodium Iodide Symporter Gene Expression
Authors: Jung Kyung Oh , Youn Hyewon , Kim Young-Hwa , Kim Seunghoo , Na Juri , Kim Yong-Il , Park Jin Woo , Kang Keon Wook , Lee Dong Soo , Chung June-Key
Published: March 2018

The therapeutic efficacy of radioiodine (131I) therapy has been reported to be variable among cancer patients and even between metastatic regions in the same patients. Because the expression level of sodium iodide symporter (NIS) cannot reflect the efficacy of therapy, other strategies are required to predict the precise therapeutic effect of 131I therapy. In this research, we investigated the correlation between iodine (I) uptake, apoptosis imaging, and therapeutic efficacy. Two HT29 cell lines, cytomegalovirus (CMV)-NIS (or NIS+++) and TERT-NIS (or NIS+), were established by retroviral transfection. I uptake was estimated by I-uptake assay and gamma camera imaging. Apoptosis was evaluated by confocal microscopy and a Maestro fluorescence imaging system (CRi Inc., Woburn, MA) using ApoFlamma (BioACTs, Seoul, Korea), a fluorescent dye–conjugated apoptosis-targeting peptide 1 (ApoPep-1). Therapeutic efficacy was determined by tumor size. The CMV-NIS showed higher I uptake and ApoFlamma signals than TERT-NIS. In xenograft models, CMV-NIS also showed high 99m technetium signals and ApoFlamma signals. Tumor reduction had a stronger correlation with apoptosis imaging signals than with gamma camera imaging signals, which reflect I uptake. Higher NIS-expressing tumors showed increased apoptosis and I uptake, resulting in a significant tumor reduction. Moreover, tumor reduction showed a strong correlation with ApoFlamma imaging compared to I-uptake imaging.
Molecular Imaging to Identify Tumor Recurrence following Chemoradiation in a Hostile Surgical Environment
Authors: Okusanya Olugbenga T. , Deshpande Charuhas , Barbosa Eduardo M. , Aggarwal Charu , Simone Charles B. , Jiang Jack , Judy Ryan , DeJesus Elizabeth , Albelda Steve , Nie Shuming , Low Philip S. , Singhal Sunil
Published: March 2018

Surgical biopsy of potential tumor recurrence is a common challenge facing oncologists, surgeons, and cancer patients. Imaging modalities have limited ability to accurately detect recurrent cancer in fields affected by previous surgery, chemotherapy, or radiation. However, definitive tissue diagnosis is often needed to initiate treatment and to direct therapy. We sought to determine if a targeted fluorescent intraoperative molecular imaging technique could be applied in a clinical setting to assist a surgical biopsy in a “hostile” field. We describe the use of a folate-fluorescein conjugate to direct the biopsy of a suspected recurrent lung adenocarcinoma invading the mediastinum that had been previously treated with chemoradiation. We found that intraoperative imaging allowed the identification of small viable tumor deposits that were otherwise indistinguishable from scar and necrosis. Our operative observations were confirmed by histology, fluorescence microscopy, and immunohistochemistry. Our results demonstrate one possible application and clinical value of intraoperative molecular imaging.
Quarter-Millimeter-Resolution Molecular Mouse Imaging with U-SPECT+
Authors: Ivashchenko Oleksandra , van der Have Frans , Villena Jose L. , Groen Harald C. , Ramakers Ruud M. , Weinans Harrie H. , Beekman Freek J.
Published: March 2018

Limited spatial resolution of preclinical positron emission tomography (PET) and single-photon emission computed tomography (SPECT) has slowed down applications of molecular imaging in small animals. Here we present the latest-generation U-SPECT system (U-SPECT+, MILabs, Utrecht, the Netherlands) enabling radionuclide imaging of mice with quarter-millimeter resolution. The system was equipped with the newest high-resolution collimator with 0.25 mm diameter circular pinholes. It was calibrated with technetium-99 m point source measurements from which the system matrix was calculated. Images were reconstructed using pixel-based ordered subset expectation maximization (OSEM). Various phantoms and mouse SPECT scans were acquired. The reconstructed spatial resolution (the smallest visible capillary diameter in a hot-rod resolution phantom) was 0.25 mm. Knee joint images show tiny structures such as the femur epicondyle sulcus, as well as a clear separation between cortical and trabecular bone structures. In addition, time-activity curves of the lumbar spine illustrated that tracer dynamics in tiny tissue amounts could be measured. U-SPECT+ allows discrimination between molecular concentrations in adjacent volumes of as small as 0.015 mL, which is significantly better than can be imaged by any existing SPECT or PET system. This increase in the level of detail makes it more and more attractive to replace ex vivo methods and allows monitoring biological processes in tiny parts of organs in vivo.
Optical Imaging Biomarkers of Drug-Induced Vascular Injury
Authors: Lin Shu-An , Suresch Donna L. , Connolly Brett , Mesfin Gebre , Gonzalez Raymond J. , Patel Manishkumar R. , Shevell Diane , Johnson Timothy , Bednar Bohumil
Published: March 2018

Drug-induced vascular injury (DIVI), defined as arterial medial degeneration/necrosis usually associated with perivascular inflammation, is frequently observed in the mesenteric arteries of rats but the relevance to humans remains a hurdle for drug development. Here, we describe the evaluation of commercially available optical imaging biomarkers using a rat DIVI model. Male Sprague Dawley rats were administered 10 mg/kg/day of a proprietary soluble guanylate cyclase activator (sGCa). Optical agents, AngioSense for the detection of vessel permeability, MMPSense for the detection of activated matrix metalloproteinases (MMPs), and IntegriSense for the detection of αvβ3 integrin, were injected via tail vein 24 hours before fluorescence (FL) ex vivo imaging. Imaging found a statistically significant difference in FL from all optical agents between treated and vehicle groups (p < .05). Mesenteric arteries were further analyzed by histopathology, flow cytometry, and immunohistochemistry. Histopathology confirmed perivascular inflammation and/or arterial medial degeneration in the sGCa-treated animals. Flow cytometry of digested arteries revealed myeloid cells as a main source of MMPSense signal. Immunohistochemical analysis further identified elevated MMP-9 expression within arterial walls and surrounding tissue of treated animals. Together, these data demonstrate that MMPSense and AngioSense are sensitive optical imaging biomarkers for the quantification of DIVI in rat mesenteric arteries.
Synthesis and Evaluation of Optical and PET GLP-1 Peptide Analogues for GLP-1R Imaging
Authors: Azad Babak Behnam , Rota Vanessa , Yu Lihai , Mcgirr Rebecca , Amant André H. St. , Lee Ting-Yim , Dhanvantari Savita , Luyt Leonard G.
Published: March 2018

A fluorescein-GLP-1 (7-37) analog was generated to determine GLP-1R distribution in various cell types of the pancreas in both strains of mice and receptor-specific uptake was confirmed by blocking with exendin-4. Biodistribution studies were carried out using 68Ga-labeled GLP-1 (7-37) peptides in CD1 and C57BL/6 mice. In addition, immunocompromised mice bearing GLP-1R-expressing insulinomas were evaluated by positron emission tomography (PET) imaging and ex vivo biodistribution studies. The optical GLP-1 probe strongly colocalized with immunofluorescence for insulin and glucagon, and more weakly with amylase (exocrine pancreas) and cytokeratin 19 (ductal cells), confirming its application for in situ GLP-1R imaging in various pancreatic cell types. Insulinomas were clearly visualized by in vivo PET. Reducing the peptide positive charge decreased renal retention as well as tumor uptake. Results demonstrate the application of the developed GLP-1 peptide analogues for in situ (optical) and in vivo (PET) imaging of GLP-1R expression.
Molecular Imaging of the Human Pulmonary Vascular Endothelium Using an Adrenomedullin Receptor Ligand
Authors: Harel François , Levac Xavier , Nguyen Quang T. , Létourneau Myriam , Marcil Sophie , Finnerty Vincent , Cossette Mariève , Fournier Alain , Dupuis Jocelyn
Published: March 2018

This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans ( N = 20) were included into escalating groups of 5 mCi ( n = 5), 10 mCi ( n = 5), or 15 mCi ( n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.
Irbesartan Attenuates Atherosclerosis in Watanabe Heritable Hyperlipidemic Rabbits: Noninvasive Imaging of Inflammation by 18F-Fluorodeoxyglucose Positron Emission Tomography
Authors: Zhao Yan , Fukao Keita , Zhao Songji , Watanabe Ayahisa , Hamada Tadateru , Yamasaki Kazuaki , Shimizu Yoichi , Kubo Naoki , Ukon Naoyuki , Nakano Toru , Tamaki Nagara , Kuge Yuji
Published: March 2018

The purpose of this study was to assess the usefulness of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in evaluating the antiatherogenic effects of irbesartan, an angiotensin II type 1 receptor blocker. Watanabe heritable hyperlipidemic rabbits were divided into the irbesartan-treated group (75 mg/kg/d; n = 14) and the control group ( n = 14). After a 9-month treatment, rabbits underwent 18F-FDG PET. Using the aortic lesions, autoradiography and histologic examinations were performed. PET imaging clearly visualized the thoracic lesions of control rabbits and showed a significant decrease in the 18F-FDG uptake level of irbesartan-treated rabbits (78.8% of controls; p < .05). Irbesartan treatment significantly reduced the plaque size (43.1% of controls) and intraplaque macrophage infiltration level (48.1% of controls). The 18F-FDG uptake level in plaques positively correlated with the plaque size ( r = .65, p < .05) and macrophage infiltration level ( r = .57, p < .05). Noninvasive imaging by 18F-FDG PET is useful for evaluating the therapeutic effects of irbesartan and reflects inflammation, a key factor involved in the therapeutic effects.
Radiosynthesis and Preliminary Biological Evaluation of [18F]VC701, a Radioligand for Translocator Protein
Authors: Di Grigoli Giuseppe , Monterisi Cristina , Belloli Sara , Masiello Valeria , Politi Letterio Salvatore , Valenti Salvatore , Paolino Marco , Anzini Maurizio , Matarrese Mario , Cappelli Andrea , Moresco Rosa Maria
Published: March 2018

Positron emission tomography (PET) can be used to monitor in vivo translocator protein (TSPO) expression by using specific radioligands. Recently, several [11C]PK11195 analogues have been synthesized to improve binding stability and brain availability. [18F]VC701 was synthesized and validated in CD healthy rats by biodistribution and inhibition analysis. Imaging studies were also conducted on animals injected unilaterally in the striatum with quinolinic acid (QA) to evaluate the TSPO ligand uptake in a neuroinflammation/neurodegenerative model. [18F]VC701 was synthesized with a good chemical and radiochemical purity and specific activity higher than 37 GBq/μmol. Kinetic studies performed on healthy animals showed the highest tracer biodistribution in TSPO-rich organs, and preadministration of cold PK11195 caused an overall radioactivity reduction. Metabolism studies showed the absence of radiometabolites in the rat brain of QA lesioned rats, and biodistribution analysis revealed a progressive increase in radioactivity ratios (lesioned to nonlesioned striatum) during time, reaching an approximate value of 5 4 hours after tracer injection. These results encourage further evaluation of this TSPO radioligand in other models of central and peripheral diseases.
EphA2 as a Diagnostic Imaging Target in Glioblastoma: A Positron Emission Tomography/Magnetic Resonance Imaging Study
Authors: Puttick Simon , Stringer Brett W. , Day Bryan W. , Bruce Zara C. , Ensbey Kathleen S. , Mardon Karine , Cowin Gary J. , Thurecht Kristofer J. , Whittaker Andrew K. , Fay Michael , Boyd Andrew W. , Rose Stephen
Published: March 2018

Noninvasive imaging is a critical technology for diagnosis, classification, and subsequent treatment planning for patients with glioblastoma. It has been shown that the EphA2 receptor tyrosine kinase (RTK) is overexpressed in a number of tumors, including glioblastoma. Expression levels of Eph RTKs have been linked to tumor progression, metastatic spread, and poor patient prognosis. As EphA2 is expressed at low levels in normal neural tissues, this protein represents an attractive imaging target for delineation of tumor infiltration, providing an improved platform for image-guided therapy. In this study, EphA2-4B3, a monoclonal antibody specific to human EphA2, was labeled with 64Cu through conjugation to the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The resulting complex was used as a positron emission tomography (PET) tracer for the acquisition of high-resolution longitudinal PET/magnetic resonance images. EphA2-4B3-NOTA-64Cu images were qualitatively and quantitatively compared to the current clinical standards of [18F]FDOPA and gadolinium (Gd) contrast–enhanced MRI. We show that EphA2-4B3-NOTA-64Cu effectively delineates tumor boundaries in three different mouse models of glioblastoma. Tumor to brain contrast is significantly higher in EphA2-4B3-NOTA-64Cu images than in [18F]FDOPA images and Gd contrast–enhanced MRI. Furthermore, we show that nonspecific uptake in the liver and spleen can be effectively blocked by a dose of nonspecific (isotype control) IgG.
Vulnerable Plaque Detection and Quantification with Gold Particle–Enhanced Computed Tomography in Atherosclerotic Mouse Models
Authors: De Wilde David , Trachet Bram , Van der Donckt Carole , Vandeghinste Bert , Descamps Benedicte , Vanhove Christian , De Meyer Guido R. Y. , Segers Patrick
Published: March 2018

Recently, an apolipoprotein E–deficient (ApoE−/−) mouse model with a mutation (C1039G+/−) in the fibrillin-1 ( Fbn1) gene (ApoE−/−Fbn1C1039G+/− mouse model) was developed showing vulnerable atherosclerotic plaques, prone to rupture, in contrast to the ApoE−/− mouse model, where mainly stable plaques are present. One indicator of plaque vulnerability is the level of macrophage infiltration. Therefore, this study aimed to measure and quantify in vivo the macrophage infiltration related to plaque development and progression. For this purpose, 5-weekly consecutive gold nanoparticle–enhanced micro–computed tomography (microCT) scans were acquired. Histology confirmed that the presence of contrast agent coincided with the presence of macrophages. Based on the microCT scans, regions of the artery wall with contrast agent present were calculated and visualized in three dimensions. From this information, the contrast-enhanced area and contrast-enhanced centerline length were calculated for the branches of the carotid bifurcation (common, external, and internal carotid arteries). Statistical analysis showed a more rapid development and a larger extent of plaques in the ApoE−/−Fbn1C1039G+/− compared to the ApoE−/− mice. Regional differences between the branches were also observable and quantifiable. We developed and applied a methodology based on gold particle–enhanced microCT to visualize the presence of macrophages in atherosclerotic plaques in vivo.
Preclinical Positron Emission Tomographic Imaging of Acute Hyperoxia Therapy of Chronic Hypoxia during Pregnancy
Authors: Zheleznyak Alexander , Garbow Joel R. , Neeman Michal , Lapi Suzanne E.
Published: March 2018

The goal of this work was to study the efficacy of the positron emission tomography (PET) tracers 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]ATSM) and in monitoring placental and fetal functional response to acute hyperoxia in late-term pregnant mice subjected to experimentally induced chronic hypoxia. E15 mice were maintained at 12% inspired oxygen for 72 hours and then imaged during oxygen inhalation with either [18F]FDG to monitor nutrient transport or 64Cu-ATSM to establish the presence of hypoxia. Computed tomography (CT) with contrast allowed clear visualization of both placentas and fetuses. The average ratio of fetal to placental [18F]FDG uptake was 0.45 ± 0.1 for the hypoxic animals and 0.55 ± 0.1 for the normoxic animals, demonstrating a significant decrease ( p = .0002) in placental function in dams exposed to chronic hypoxic conditions. Hypoxic placentas and fetuses retained more 64Cu-ATSM compared to normoxic placentas and fetuses. Herein we report first-in-mouse PET imaging of fetuses employing both tracers [18F]FDG (metabolism) and 64Cu-ATSM (hypoxia). [18F]FDG PET/CT imaging allowed clear visualization of placental-fetal structures and supported quantification of tracer uptake, making this a sensitive tool for monitoring placental function in preclinical rodent models. These measurements illustrate the potentially irreversible damage generated by chronic exposure to hypoxia, which cannot be corrected by acute exposure to hyperoxia.
Cyclotron Production of High–Specific Activity 55Co and In Vivo Evaluation of the Stability of 55Co Metal-Chelate-Peptide Complexes
Authors: Mastren Tara , Marquez Bernadette V. , Sultan Deborah E. , Bollinger Elizabeth , Eisenbeis Paul , Voller Tom , Lapi Suzanne E.
Published: March 2018

This work describes the production of high–specific activity 55Co and the evaluation of the stability of 55Co-metal-chelate-peptide complexes in vivo. 55Co was produced via the 58Ni(p,α)55Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/μmol. 55Co-DO3A and 55Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/μg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET) and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55CoCl2. Both 55Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers’ uptake in the liver by sixfold at 24 hours with ˜ 1% ID/g and at 48 hours with ˜ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ˜ 0.7% ID/g and sevenfold at 48 hours with ˜ 0.35% ID/g. These results support the use of 55Co as a promising new radiotracer for PET imaging of cancer and other diseases.
PET Imaging of Steroid Hormone Receptor Expression
Authors: Allott Louis , Smith Graham , Aboagye Eric O. , Carroll Laurence
Published: March 2018

Steroid hormone receptor (SHR) expression and changes in SHR expression compared to basal levels, whether upregulated, down-regulated, or mutated, form a distinguishing feature of some breast, ovarian, and prostate cancers. These receptors act to induce tumor proliferation. In the imaging context, total expression together with modulation of expression can yield predictive and prognostic information. Currently, biopsy for histologic assessment of SHR expression is routine for breast and prostate cancer; however, the technique is not well suited to the heterogeneous tumor environment and can lead to incorrect receptor expression assignment, which precludes effective treatment. The development of positron emission tomography (PET) radioligands to image receptor expression may overcome the difficulties associated with tumor heterogeneity and facilitate the assessment of metastatic disease.
Initial Assessment of β3-Adrenoceptor-Activated Brown Adipose Tissue in Streptozotocin-Induced Type 1 Diabetes Rodent Model Using [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography
Authors: Baranwal Aparna , Mirbolooki M. Reza , Mukherjee Jogeshwar
Published: March 2018

Metabolic activity of brown adipose tissue (BAT) is activated by β3-adrenoceptor agonists and norepinephrine transporter (NET) blockers and is measurable using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in rats. Using the streptozotocin (STZ)-treated rat model of type 1 diabetes mellitus (T1DM), we investigated BAT activity in this rat model under fasting and nonfasting conditions using [18F]FDG PET/CT. Drugs that enhance BAT activity may have a potential for therapeutic development in lowering blood sugar in insulin-resistant diabetes. Rats were rendered diabetic by administration of STZand confirmed by glucose measures. [18F]FDG was injected in the rats (fasted or nonfasted) pretreated with either saline or β3-adrenoceptor agonist CL316,243 or the NET blocker atomoxetine for PET/CT scans. [18F]FDG metabolic activity was computed as standard uptake values (SUVs) in interscapular brown adipose tissue (IBAT) and compared across the different drug treatment conditions. Blood glucose levels > 500 mg/dL were established for the STZ-treated diabetic rats. Under fasting conditions, average uptake of [18F]FDG in the IBAT of STZ-treated diabetic rats was approximately 70% lower compared to that of normal rats. Both CL316,243 and atomoxetine activated IBAT in normal rats had an SUV > 5, whereas activation in STZ-treated rats was significantly lower. The agonist CL316,243 activated IBAT up to threefold compared to saline in the fasted STZ-treated rat. In the nonfasted rat, the IBAT activation was up by twofold by CL316243. Atomoxetine had a greater effect on lowering blood sugar levels compared to CL316,243 in the nonfasted rats. A significant reduction in metabolic activity was observed in the STZ-treated diabetic rodent model. Increased IBAT activity in the STZ-treated diabetic rat under nonfasted conditions using the β3-adrenoceptor agonist CL316,243 suggests a potential role of BAT in modulating blood sugar levels. Further studies are needed to evaluate the therapeutic role of β3-adrenoceptor agonists in insulin-resistant T1DM.
Digital Microfluidics: A New Paradigm for Radiochemistry
Authors: Keng Pei Yuin , van Dam R. Michael
Published: March 2018

The emerging technology of digital microfluidics is opening up the possibility of performing radiochemistry at the microliter scale to produce tracers for positron emission tomography (PET) labeled with fluorine-18 or other isotopes. Working at this volume scale not only reduces reagent costs but also improves specific activity (SA) by reducing contamination by the stable isotope. This technology could provide a practical means to routinely prepare high-SA tracers for applications such as neuroimaging and could make it possible to routinely achieve high SA using synthesis strategies such as isotopic exchange. Reagent droplets are controlled electronically, providing high reliability, a compact control system, and flexibility for diverse syntheses with a single-chip design. The compact size may enable the development of a self-shielded synthesizer that does not require a hot cell. This article reviews the progress of this technology and its application to the synthesis of PET tracers.