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1.  Molecular Imaging Detects Impairment in the Retrograde Axonal Transport Mechanism After Radiation Induced Spinal Cord Injury 
Purpose
The goal of this study was to determine whether molecular imaging of retrograde axonal transport is a suitable technique to detect changes in the spinal cord in response to radiation injury.
Procedures
The lower thoracic spinal cords of adult female BALB/c mice were irradiated with single doses of 2, 10, or 80 Gy. An optical imaging method was used to observe the migration of the fluorescently labeled non-toxic C-fragment of tetanus toxin (TTc) from an injection site in the calf muscles to the spinal cord. Changes in migration patterns compared to baseline and controls allowed assessment of radiation-induced alterations in the retrograde neuronal axonal transport mechanism. Subsequently, tissues were harvested and histological examination of the spinal cords performed.
Results
Transport of TTc in the thoracic spinal cord was impaired in a dose-dependent manner. Transport was significantly decreased by 16 d in animals exposed to either 10 or 80 Gy, while animals exposed to 2 Gy were affected only minimally. Further, animals exposed to the highest dose also experienced significant weight loss by 9 d and developed posterior paralysis by 45 d. Marked histological changes including vacuolization and white matter necrosis were observed in radiated cords after 30 d for mice exposed to 80 Gy.
Conclusion
Radiation of the spinal cord induces dose-dependent changes in retrograde axonal transport, which can be monitored by molecular imaging. This approach suggests a novel diagnostic modality to assess nerve injury and monitor therapeutic interventions.
doi:10.1007/s11307-013-0713-0
PMCID: PMC4085152  PMID: 24395625
Retrograde axonal transport; Spinal cord; Radiation injury; Molecular imaging; Tetanus toxin fragment C; Demyelination
2.  A Deformable Atlas of the Laboratory Mouse 
Purpose
This paper presents a deformable mouse atlas of the laboratory mouse anatomy. This atlas is fully articulated and can be positioned into arbitrary body poses. The atlas can also adapt body weight by changing body length and fat amount.
Procedures
A training set of 103 micro-CT images was used to construct the atlas. A cage-based deformation method was applied to realize the articulated pose change. The weight-related body deformation was learned from the training set using a linear regression method. A conditional Gaussian model and thin-plate spline mapping were used to deform the internal organs following the changes of pose and weight.
Results
The atlas was deformed into different body poses and weights, and the deformation results were more realistic compared to the results achieved with other mouse atlases. The organ weights of this atlas matched well with the measurements of real mouse organ weights. This atlas can also be converted into voxelized images with labeled organs, pseudo CT images and tetrahedral mesh for phantom studies.
Conclusions
With the unique ability of articulated pose and weight changes, the deformable laboratory mouse atlas can become a valuable tool for preclinical image analysis.
doi:10.1007/s11307-014-0767-7
PMCID: PMC4353592  PMID: 25049072
Small animal imaging; Mouse atlas; Articulated model; Atlas registration; Molecular imaging
3.  Axl-Targeted Cancer Imaging with Humanized Antibody h173 
Purpose
The tyrosine kinase receptor Axl is overexpressed in various types of cancer and correlated with cancer malignancy. Selective Axl blockade reduces tumor growth and metastasis. The purpose of this study was to examine whether the humanized anti-Axl antibody humanized 173 (h173) labeled with near-infrared fluorescence (NIRF) dye Cy5.5 could be applied as a molecular imaging probe for NIRF imaging of Axl expression in tumor models.
Procedures
NIRF dye Cy5.5 was conjugated to h173 or human normal immunoglobulin G (hIgG) control through amino groups. The resulting probes were evaluated in both A549 (Axl positive) and NCI-H249 (Axl negative) lung cancer xenografts through in vivo NIRF imaging. Ex vivo imaging and probe distribution assay were also carried out to confirm the in vivo imaging results.
Results
After conjugation, binding activity of h173-Cy5.5 was determined to be 97.75 %± 2.09 % of the unmodified h173. In vitro fluorescence-activated cell sorting (FACS) and fluorescence microscopy analysis validated the specific binding of h173 toward Axl-positive A549 cells. h173-Cy5.5 was then applied to image Axl expression in vivo. In A549 (Axl positive) cancer xenografts, the tumor uptake of h173-Cy5.5 was significantly higher than that of the hIgG-Cy5.5 control (P<0.05) at late time points (1, 2, 3, 4, and 7 days). On the contrary, in NCI-H249 (Axl negative) cancer xenografts, the tumor uptake of both hIgG-Cy5.5 and h173-Cy5.5 was low and showed no significant difference (P>0.05) at all time points examined. Ex vivo imaging and immunofluorescence staining analysis further validated the in vivo imaging results.
Conclusions
Collectively, all in vitro, in vivo, and ex vivo data suggested that h173-Cy5.5 could serve as a valid probe for Axl-targeted cancer imaging, which could therefore aid in tumor diagnosis, prognosis, and treatment monitoring.
doi:10.1007/s11307-013-0714-z
PMCID: PMC4183751  PMID: 24424460
Axl receptor; Near-infrared fluorescence (NIRF) imaging; Antibody; Cancer
4.  Evaluation of [111In]-Labeled Zinc-Dipicolylamine Tracers for SPECT Imaging of Bacterial Infection 
Purpose
This study prepared three structurally related zinc-dipicolylamine (ZnDPA) tracers with [111In] labels and conducted biodistribution and SPECT/CT imaging studies of a mouse leg infection model.
Methods
Two monovalent tracers, ZnDPA-[111In]DTPA and ZnDPA-[111In]DOTA, each with a single zinc-dipicolylamine targeting unit, and a divalent tracer, Bis(ZnDPA)-[111In]DTPA,with two zinc-dipicolylamine units were prepared. Organ biodistribution and SPECT/CT imaging studies were performed on living mice with a leg infection created by injection of clinically relevant Gram positive Streptococcus pyogenes. Fluorescent and luminescent Eu3+-labeled versions of these tracers were also prepared and used to measure relative affinity for the exterior membrane surface of bacterial cells and mimics of healthy mammalian cells.
Results
All three 111In-labeled radiotracers were prepared with radiopurity > 90%. The biodistribution studies showed that the two monovalent tracers were cleared from the body through the liver and kidney, with retained % injected dose for all organs of < 8 % at 20 hours and infected leg T/NT ratio of ≤ 3.0. Clearance of the divalent tracer from the bloodstream was slower and primarily through the liver, with a retained % injected dose for all organs < 37% at 20 hours and T/NT ratio rising to 6.2 after 20 hours. The SPECT/CT imaging indicated the same large difference in tracer pharmacokinetics and higher accumulation of the divalent tracer at the site of infection.
Conclusions
All three [111In]-ZnDPA tracers selectively targeted the site of a clinically relevant mouse infection model that could not be discerned by visual external inspection of the living animal. The highest target selectivity, observed with a divalent tracer equipped with two zinc-dipicolylamine targeting units, compares quite favorably with the imaging selectivities previously reported for other nuclear tracers that target bacterial cell surfaces. The tracer pharmacokinetics depended heavily on tracer molecular structure suggesting that it may be possible to rapidly fine-tune the structural properties for optimized in vivo imaging performance and clinical translation.
doi:10.1007/s11307-014-0758-8
PMCID: PMC4515950  PMID: 25115869
Zinc-dipicolylamine; infection imaging; SPECT/CT; 111-indium; molecular tracer
5.  Magnetomotive Optical Coherence Tomography for the Assessment of Atherosclerotic Lesions Using αvβ3 Integrin-Targeted Microspheres 
Purpose
We investigated the early-stage fatty streaks/plaques detection using magnetomotive optical coherence tomography (MM-OCT) in conjunction with αvβ3 integrin-targeted magnetic microspheres (MSs). The targeting of functionalized MSs was investigated by perfusing ex vivo aortas from an atherosclerotic rabbit model in a custom-designed flow chamber at physiologically relevant pulsatile flow rates and pressures.
Procedures
Aortas were extracted and placed in a flow chamber. Magnetic MS contrast agents were perfused through the aortas and MM-OCT, fluorescence confocal, and bright field microscopy were performed on the ex vivo aorta specimens for localizing the MSs.
Results
The results showed a statistically significant and stronger MM-OCT signal (3.30±1.73 dB) from the aorta segment perfused with targeted MSs, compared with the nontargeted MSs (1.18±0.94 dB) and control (0.78±0.41 dB) aortas. In addition, there was a good co-registration of MM-OCT signals with confocal microscopy.
Conclusions
Early-stage fatty streaks/plaques have been successfully detected using MM-OCT in conjunction with αvβ3 integrin-targeted magnetic MSs.
doi:10.1007/s11307-013-0671-6
PMCID: PMC4495956  PMID: 23907212
Optical coherence tomography; Magnetomotive; Protein microspheres; Fatty streaks; Atherosclerosis; αvβ3 integrin; Flow chamber
6.  Non-invasive detection of macrophages in atheroma using a radiocontrast-loaded phosphatidylserine-containing liposomal contrast agent for computed tomography 
Purpose
Macrophage plays an important role in plaque destabilization in atherosclerosis. By harnessing the affinity of macrophages to certain phospholipid species, a liposomal contrast agent containing phosphatidylserine (PS) and computed tomographic (CT) contrast agent was prepared and evaluated for CT imaging of plaque-associated macrophages in rabbit models of atherosclerosis.
Procedures
Liposomes containing PS and iodixanol were evaluated for their physicochemical characteristics, in vitro macrophage uptake, in vivo blood pool clearance and organ distribution. Plaque enhancement in the aorta was imaged with computed tomography (CT) in two atherosclerotic rabbit models.
Results
In vitro macrophage uptake of PS-liposomes increased with increasing amount of PS in the liposomes. Overall clearance of PS-liposomes was more rapid than control liposomes. Smaller PS-liposomes (d = 112 ± 4 nm) were more effective than control liposomes of similar size or larger control and PS-liposomes (d = 172 ± 17 nm) in enhancing aortic plaques in both rabbit models.
Conclusions
Proper liposomal surface modification and appropriate sizing are important determinant for CT-based molecular imaging of macrophages in atheroma.
doi:10.1007/s11307-014-0798-0
PMCID: PMC4393348  PMID: 25301703
Atherosclerosis; Macrophage; Molecular Imaging; Computed Tomography; Apoptosis; Inflammation; Liposomes
7.  Monitoring Dynamic Interactions between Breast Cancer Cells and Human Bone Tissue in a Co-Culture Model 
Purpose
Bone is a preferential site of breast cancer metastasis and models are needed to study this process at the level of the microenvironment. We have used bioluminescence imaging (BLI) and multiplex biomarker immunoassays to monitor dynamic breast cancer cell behaviors in co-culture with human bone tissue.
Procedures
Femur tissue fragments harvested from hip replacement surgeries were co-cultured with luciferase-positive MDA-MB-231-fLuc cells. BLI was performed to quantify breast cell division and track migration relative to bone tissue. Breast cell colonization of bone tissues was assessed with immunohistochemistry. Biomarkers in co-culture supernatants were profiled with MILLIPLEX® immunoassays.
Results
BLI demonstrated increased MDA-MB-231-fLuc proliferation (p<0.001) in the presence vs. absence of bones, and revealed breast cell migration toward bone. Immunohistochemistry illustrated MDA-MB-231-fLuc colonization of bone, and MILLIPLEX® profiles of culture supernatants suggested breast/bone crosstalk.
Conclusions
Breast cell behaviors that facilitate metastasis occur reproducibly in human bone tissue co-cultures and can be monitored and quantified using BLI and multiplex immunoassays.
doi:10.1007/s11307-013-0685-0
PMCID: PMC4486376  PMID: 24008275
8.  NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of FLT as a Marker of Proliferation in Patients with Recurrent Gliomas: Safety Studies 
Purpose
3’-[F-18]Fluoro-3’-deoxythymidine (FLT) is an analog of thymidine that is being developed for imaging cellular proliferation. The goal of this study was to prove that the dose of FLT used for positron emission tomography imaging produces no significant toxicity.
Procedures
Twelve patients with gliomas with either recurrence or suspected radionecrosis were imaged with FLT. Before and at several time points after imaging, subjects underwent general physical and neurological examinations with review of systems and tests of hematologic, hepatic, renal, and several other metabolic parameters. Vital signs and electrocardiograms were monitored during and after the imaging session.
Results
There were no significant adverse effects from FLT injected at a dose of 0.07 mCi/kg (maximum of 5 mCi) at specific activities of 1.25 Ci/µmol or higher. The FLT mass administered for imaging was 0.0001% to 0.0009% of the least toxic cumulative dose administered in clinical trials of FLT as an antiretroviral agent.
Conclusions
FLT is a safe radiotracer for quantifying proliferation in the human cancer setting.
doi:10.1007/s11307-008-0151-6
PMCID: PMC4465245  PMID: 18543042
3’-[F-18]fluoro-3’-deoxythymidine; FLT; Fluorothymidine; Positron emission tomography (PET); Glioma; Glioblastoma; Safety; Toxicity; Proliferation
9.  Functional Imaging of Cerebral Blood Flow and Glucose Metabolism in Parkinson’s Disease and Huntington’s Disease 
Brain imaging of cerebral blood flow and glucose metabolism has been playing key roles in describing pathophysiology of Parkinson’s disease (PD) and Huntington’s disease (HD), respectively. Many biomarkers have been developed in recent years to investigate the abnormality in molecular substrate, track the time course of disease progression, and evaluate the efficacy of novel experimental therapeutics. A growing body of literature has emerged on neurobiology of these two movement disorders in resting states and in response to brain activation tasks. In this paper, we review the latest applications of these approaches in patients and normal volunteers at rest conditions. The discussions focus on brain mapping studies with univariate and multivariate statistical analyses on a voxel basis. In particular, we present data to validate the reproducibility and reliability of unique spatial covariance patterns related with PD and HD.
doi:10.1007/s11307-007-0085-4
PMCID: PMC4455550  PMID: 17334854
Neurodegenerative disorders; Parkinson’s disease; Huntington’s disease; Cerebral blood flow; Metabolism; Brain mapping; Spatial covariance analysis
10.  Assessment of global cardiac uptake of Radiolabeled Iron Oxide Nanoparticles in Apolipoprotein E-Deficient Mice: implications for imaging cardiovascular inflammation 
Purpose
Atherosclerosis is a leading cause of death in industrialized countries and is characterized by the accumulation of lipids and inflammatory cells, including macrophages, in blood vessel walls. Therefore, the ability to image macrophages could help identify plaques that are precursors of acute thrombotic events. Previous research has shown that long-circulating, nanoparticles could be used to detect macrophages within atherosclerotic plaques of the aorta. By conducting this study, we investigated whether global cardiac uptake of radiolabeled nanoparticles could allow assessment of total macrophage burden in the coronary arteries.
Procedures
Dextran-coated Iron Oxide Nanoparticles (IONPs) were labeled with iodine-125 via Bolton-Hunter (SHPP) method. IONPs were characterized by means of dynamic light scattering and transmission electronic microscopy. Biodistribution studies were performed in healthy and atherosclerotic mice. Additionally, digital autoradiography of hearts from both healthy and atherosclerotic mice was performed to assess regional and global atherosclerotic burden.
Results
The [125I]IONPs exhibited high radiolabel stability and long blood circulation, which eventually led to high heart uptake in apoE −/− mice when compared with healthy controls. Furthermore, digital autoradiography showed substantially enhanced emission of signals from the hearts of atherosclerotic mice, while no or minimal cardiac signals were detected in healthy mice.
Conclusions
This preparation showed adequate physical-chemical properties for in vivo studies, such as small size (~30 nm), good radiolabel stability, and long circulation time. There was also significant accumulation in the heart of apoE−/− mice compared with that of healthy control animals. These findings suggest that radiolabeled dextran-coated iron oxide nanoparticles may have potential to become a useful tool to detect macrophages in the atherosclerosis plaques of coronary arteries; however, these preliminary findings should be confirmed by further studies in a larger scale in various atherosclerosis models.
doi:10.1007/s11307-013-0709-9
PMCID: PMC4016162  PMID: 24297372
Atherosclerosis; Radiolabeled nanoparticles; Diagnosis; Iron oxide nanoparticles; Global heart uptake
11.  Comparison of [18F]DCFPyL and [68Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with Relapsed Prostate Cancer 
Molecular Imaging and Biology  2015;17(4):575-584.
Purpose
Gallium-68 (Ga-68)-labeled tracers for imaging expression of the prostate-specific membrane antigen (PSMA) such as the [68Ga]Ga-PSMA-HBED-CC have already demonstrated high potential for the detection of recurrent prostate cancer. However, compared to Ga-68, a labeling with fluorine-18 (F-18) would offer advantages with respect to availability, production amount, and image resolution. [18F]DCFPyL is a promising F-18-labeled candidate for PSMA-positron emission tomography (PET) imaging that has been recently introduced. In the current study, we aimed to compare [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL for clinical use in biochemically relapsed prostate cancer.
Procedures
In 14 selected patients with PSA relapse of prostate cancer, [18F]DCFPyL PET/X-ray computed tomography (CT) was performed in addition to [68Ga]Ga-PSMA-HBED-CC PET/CT. A systematic comparison was carried out between results obtained with both tracers with regard to the number of detected PSMA-positive lesions, the standardized uptake value (SUV)max and the lesion to background ratios.
Results
All suspicious lesions identified by [68Ga]Ga-PSMA-HBED-CC were also detected with [18F]DCFPyL. In three patients, additional lesions were observed using [18F]DCFPyL PET/CT. The mean SUVmax in the concordant [18F]DCFPyL PSMA-positive lesions was significantly higher as compared to [68Ga]Ga-PSMA-HBED-CC (14.5 vs. 12.2, p = 0.028, n = 15). The mean tumor to background ratios (n = 15) were significantly higher for [18F]DCFPyL compared to [68Ga]Ga-PSMA-HBED-CC using kidney, spleen, or parotid as reference organs (p = 0.006, p = 0.002, p = 0.008), but no significant differences were found using the liver (p = 0.167) or the mediastinum (p = 0.363) as reference organs.
Conclusion
[18F]DCFPyL PET/CT provided a high image quality and visualized small prostate lesions with excellent sensitivity. [18F]DCFPyL represents a highly promising alternative to [68Ga]Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer.
doi:10.1007/s11307-015-0866-0
PMCID: PMC4493776  PMID: 26013479
Prostate-specific membrane antigen (PSMA); F-18; Ga-68; Positron emission tomography (PET); Prostate cancer
12.  Synthesis of [18F]-labelled Maltose Derivatives as PET Tracers for Imaging Bacterial Infection 
Purpose
To develop novel positron emission tomography (PET) agents for visualization and therapy monitoring of bacterial infections.
Procedures
It is known that maltose and maltodextrins are energy sources for bacteria. Hence, 18F-labelled maltose derivatives could be a valuable tool for imaging bacterial infections. We have developed methods to synthesize 4-O-(α-D-glucopyranosyl)-6-deoxy-6-[18F]fluoro-D-glucopyranoside (6-[18F]fluoromaltose) and 4-O-(α-D-glucopyranosyl)-1-deoxy-1-[18F]fluoro-D-glucopyranoside (1-[18F]fluoromaltose) as bacterial infection PET imaging agents. 6-[18F]fluoromaltose was prepared from precursor 1,2,3-tri-O-acetyl-4-O-(2′,3′,-di-O-acetyl-4′,6′-benzylidene-α-D-glucopyranosyl)-6-deoxy-6-nosyl-D-glucopranoside (5). The synthesis involved the radio-fluorination of 5 followed by acidic and basic hydrolysis to give 6-[18F]fluoromaltose. In an analogous procedure, 1-[18F]fluoromaltose was synthesized from 2,3, 6-tri-O-acetyl-4-O-(2′,3′,4′,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-deoxy-1-O-triflyl-D-glucopranoside (9). Stability of 6-[18F]fluoromaltose in phosphate-buffered saline (PBS) and human and mouse serum at 37 °C was determined. Escherichia coli uptake of 6-[18F]fluoromaltose was examined.
Results
A reliable synthesis of 1- and 6-[18F]fluoromaltose has been accomplished with 4–6 and 5–8 % radiochemical yields, respectively (decay-corrected with 95 % radiochemical purity). 6-[18F]fluoromaltose was sufficiently stable over the time span needed for PET studies (~96 % intact compound after 1-h and ~65 % after 2-h incubation in serum). Bacterial uptake experiments indicated that E. coli transports 6-[18F]fluoromaltose. Competition assays showed that the uptake of 6-[18F]fluoromaltose was completely blocked by co-incubation with 1 mM of the natural substrate maltose.
Conclusion
We have successfully synthesized 1- and 6-[18F]fluoromaltose via direct fluorination of appropriate protected maltose precursors. Bacterial uptake experiments in E. coli and stability studies suggest a possible application of 6-[18F]fluoromaltose as a new PET imaging agent for visualization and monitoring of bacterial infections.
doi:10.1007/s11307-014-0793-5
PMCID: PMC4444077  PMID: 25277604
Bacterial infection; Imaging; Positron emission tomography; Maltose
13.  Tumor-Specific Targeting With Modified Sindbis Viral Vectors: Evaluation with Optical Imaging and Positron Emission Tomography In Vivo 
Purpose
Sindbis virus (SINV) infect tumor cells specifically and systemically throughout the body. Sindbis vectors are capable of expressing high levels of transduced suicide genes and thus efficiently produce enzymes for prodrug conversion in infected tumor cells. The ability to monitor suicide gene expression levels and viral load in patients, after administration of the vectors, would significantly enhance this tumor-specific therapeutic option.
Procedures
The tumor specificity of SINV is mediated by the 67-kDa laminin receptor (LR). We probed different cancer cell lines for their LR expression and, to determine the specific role of LR-expression in the infection cycle, used different molecular imaging strategies, such as bioluminescence, fluorescence molecular tomography, and positron emission tomography, to evaluate SINV-mediated infection in vitro and in vivo.
Results
All cancer cell lines showed a marked expression of LR. The infection rates of the SINV particles, however, differed significantly among the cell lines.
Conclusion
We used novel molecular imaging techniques to visualize vector delivery to different neoplatic cells. SINV infection rates proofed to be not solely dependent on cellular LR expression. Further studies need to evaluate the herein discussed ways of cellular infection and viral replication.
doi:10.1007/s11307-012-0585-8
PMCID: PMC4429791  PMID: 22847302
Molecular imaging; Sindbis virus; Tumor targeting; Bioluminescence; FMT; PET
14.  Syntheses and Radiosyntheses of Two Carbon-11 Labeled Potent and Selective Radioligands for Imaging Vesicular Acetylcholine Transporter 
Purpose
The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. The syntheses and C-11 labeling of two potent enantiopure VAChT inhibitors are reported here.
Procedures
Two VAChT inhibitors, (±)-2 and (±)-6, were successfully synthesized. A chiral HPLC column was used to resolve the enantiomers from each corresponding racemic mixture for in vitro characterization. The radiosyntheses of (−)-[11C]2 and (−)-[11C]6 from the corresponding desmethyl phenol precursor was accomplished using [11C]methyl iodide or [11C]methyl triflate, respectively.
Results
The synthesis of (−)-[11C]2 was accomplished with 40–50 % radiochemical yield (decay-corrected), SA>480 GBq/μmol (EOB), and radiochemical purity >99 %. Synthesis of (−)-[11C]6 was accomplished with 5–10 % yield, SA>140 GBq/μmol (EOB), and radiochemical purity >97 %. The radiosynthesis and dose formulation of each tracer was completed in 55–60 min.
Conclusions
Two potent enantiopure VAChT ligands were synthesized and 11C-labeled with good radiochemical yield and specific activity.
doi:10.1007/s11307-014-0748-x
PMCID: PMC4414325  PMID: 24875230
VAChT; Alzheimer’s disease; PET imaging; Radiotracer; Vesamicol
15.  In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter 
Purpose
The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective 11C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.
Procedures
For both (−)-[11C]2 and (−)-[11C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (−)-[11C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.
Results
The resolved enantiomers (−)-2 and (−)-6 were very potent and selective for VAChT in vitro (Ki<5 nM for VAChT with >35-fold selectivity for VAChT vs. σ receptors); both radioligands, (−)-[11C]2 and (−)-[11C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (−)-[11C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550±0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (−)-[11C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (−)-[11C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (−)-[11C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.
Conclusions
The radioligand (−)-[11C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.
doi:10.1007/s11307-014-0749-9
PMCID: PMC4404702  PMID: 24865402
VAChT; Alzheimer’s disease; PET imaging; Radiotracer; Vesamicol
16.  Comparison of PET Imaging with 64Cu-Liposomes and 18F-FDG in the 7,12-Dimethylbenz[a]anthracene (DMBA)-Induced Hamster Buccal Pouch Model of Oral Dysplasia and Squamous Cell Carcinoma 
Purpose
Currently, 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) is the gold standard radiotracer for staging of head and neck cancer; however, the low sensitivity of this tracer can impede detection of early lesions. 64Cu-liposomes accumulate in various cancers and provide both a sensitive tracer and an indication of the biodistribution of nanotherapeutics. Here, the accumulation of 64Cu-liposomes in early and established cancers is assessed and compared with 18F-FDG in a head and neck cancer model.
Methods
Lesions ranging from mild dysplasia to squamous cell carcinoma were induced in a hamster model of head and neck cancer by topical application of 7,12-dimethylbenz[a]anthracene to the buccal pouch. The hamsters were imaged with micro-positron emission tomography using 18F-FDG and 64Cu-liposomes.
Results
At 24 h postinjection, 64Cu-liposome accumulation exceeded the accumulation of 18F-FDG in every pathologic grade. The lesion-to-cheek pouch (background) ratio and lesion-to-brain ratio were also higher for 64Cu-liposomes than for 18F-FDG.
Conclusion
Imaging of a nanotracer such as 64Cu-liposomes can improve the visualization of head and neck tumors. Accumulation of liposomal particles in head and neck tumors over various pathologic grades averaged 3.5 %ID/cc demonstrating the potential for liposomal therapy with targeted chemotherapeutic agents.
doi:10.1007/s11307-013-0676-1
PMCID: PMC3984137  PMID: 24019092
Liposomes; Head and neck cancer; Positron emission tomography
17.  Comparison of 4D-microSPECT and microCT for murine cardiac function 
Purpose
The objective of this study was to compare a new generation of four-dimensional (4D) microSPECT with microCT for quantitative in vivo assessment of murine cardiac function.
Procedures
4D isotropic cardiac images were acquired from normal C57BL/6 mice with either microSPECT at 350-micron resolution (n=6) or microCT at 88-micron resolution (n=6). One additional mouse with myocardial infarction (MI) was scanned with both modalities. Prior to imaging, mice were injected with either 99mTc -tetrofosmin for microSPECT, or a liposomal blood pool contrast agent for microCT. Segmentation of the left ventricle (LV) was performed using Vitrea (Vital Images) software, to derive global and regional function.
Results
Measures of global LV function between microSPECT and microCT groups were comparable (e.g. ejection fraction=71±6%-microSPECT and 68±4%-microCT). Regional functional indices (wall motion, wall thickening, regional ejection fraction) were also similar for the two modalities. In the mouse with MI, microSPECT identified a large perfusion defect that was not evident with microCT.
Conclusions
Despite lower spatial resolution, microSPECT was comparable to microCT in the quantitative evaluation of cardiac function. MicroSPECT offers an advantage over microCT in the ability to evaluate myocardial perfusion radiotracer distribution and function simultaneously. MicroSPECT should be considered as an alternative to microCT and MR for preclinical cardiac imaging in the mouse.
doi:10.1007/s11307-013-0686-z
PMCID: PMC4061569  PMID: 24037175
18.  Preclinical imaging evaluation of novel TSPO-PET ligand 2-(5,7-diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1008) in glioma 
Purpose
Translocator protein (TSPO) concentrations are elevated in glioma, suggesting a role for TSPO Positron Emission Tomography (PET) imaging in this setting. In preclinical PET studies, we evaluated a novel, high-affinity TSPO PET ligand, [18F]VUIIS1008, in healthy mice and glioma-bearing rats.
Procedures
Dynamic PET data were acquired simultaneously with [18F]VUIIS1008 injection, with binding reversibility and specificity evaluated in vivo by non-radioactive ligand displacement or blocking. Compartmental analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.
Results
[18F]VUIIS1008 exhibited rapid uptake in TSPO-rich organs. PET ligand uptake was displaceable with non-radioactive VUIIS1008 or PBR06 in mice. Tumor accumulation of [18F]VUIIS1008 was blocked by pre-treatment with VUIIS1008 in rats. [18F]VUIIS1008 exhibited improved tumor-to-background ratio and higher binding potential in tumors compared to a structurally similar pyrazolopyrimidine TSPO ligand, [18F]DPA-714.
Conclusions
The PET ligand [18F]VUIIS1008 exhibits promising characteristics as a tracer for imaging glioma. Further translational studies appear warranted.
doi:10.1007/s11307-014-0743-2
PMCID: PMC4372299  PMID: 24845529
PET; DPA-714; VUIIS1008; TSPO; glioma; cancer imaging
19.  A genetic strategy for combined screening and localized imaging of breast cancer 
PURPOSE
Improvements are needed for the early detection of breast cancer, as current imaging methods lack sensitivity to detect small tumors and assess their disease phenotype.
PROCEDURES
To address this issue the dual reporter adenoviral vector (Ad5/3-Id1-SEAP-Id1-mCherry) was produced with a cancer specific Id1 promoter driving expression of a blood-based screening reporter (secreted embryonic alkaline phosphatase, SEAP) and a fluorescent imaging reporter (mCherry). This diagnostic system was assessed for its screening potential on breast cancer cell lines of various aggressive phenotypes. Reporter expression was measured and correlated with promoter level expression using western blot. Adenovirus receptor expression was normalized against reporter expression with luciferase infectivity assays. Ad5/3-Id1-SEAP-Id1-mCherry infected MDA-MB-231 cells combined with uninfected cells were implanted into the mammary fat pad of athymic nude mice to recapitulate low dose tumor delivery. Id1 driven SEAP expression and mCherry imaging were monitored to validate diagnostic sensitivity and efficacy.
RESULTS
Infected breast cancer cell lines displayed SEAP levels in the media that were 10-fold above background by 2 days after infection. Ad5/3-Id1-SEAP-Id1-mCherry infected cells (MOI=10) implanted in athymic nude mice demonstrated a 14-fold increase in serum SEAP levels over baseline when as little as 2.5% of the tumor contained infected cells. This robust response was also found for the mCherry reporter which was clearly visible in tumor xenografts on day 2 post implantation.
CONCLUSIONS
This diagnostic system that combines screening with imaging for early detection and monitoring of breast cancer can be easily extended to other reporters/modalities and cancer-targeting methods. Combining screening with imaging in a genetic, cancer-specific mechanism allows sensitive multi-modal detection and localization of breast cancer.
doi:10.1007/s11307-010-0377-y
PMCID: PMC4359509  PMID: 20658194
20.  The Relationship between Patients’ Serum Glucose Levels and Metabolically Active Brown Adipose Tissue Detected by PET/CT 
Purpose
To compare blood glucose levels in patients with or without “detectable” brown adipose tissue (BAT) using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/ computed tomography (FDG PET/CT).
Procedures
Nine hundred eight patients had PET/CT scans and were previously identified as having, or not having, FDG uptake in BAT. The original database was retrospectively reviewed for blood glucose level and body mass index (BMI) at the time of imaging. Blood glucose levels were compared between patients with or without FDG uptake in BAT, adjusting for age, sex, and BMI.
Results
Fifty-six patients (6.2%) had FDG uptake in BAT. In the univariate analysis, patients without FDG uptake in BAT had a higher risk of glucose ≥100 mg/dL (odds ratio 3.4, 95% CI= 1.6–7.3; P=0.0007). After adjustment for age, sex, BMI, and significant interaction of sex and BMI, patients without BAT tended to have a higher risk of glucose ≥100 mg/dL, although not statistically significant (odds ratio=1.6, 95% CI=0.7–3.6; P=0.268).
Conclusions
Although causal relationships are not specified, the data suggest that BAT uptake, glucose levels, BMI, sex, and age are inter-related and the possibility that presence of “detectable” BAT is protective against diabetes and obesity. FDG PET/CT may be a vital tool for further investigations of diabetes and obesity.
doi:10.1007/s11307-010-0379-9
PMCID: PMC4352310  PMID: 21140233
Brown fat; BAT; Glucose; FDG; “USA”-Fat; PET; Brown adipose tissue
21.  Effects of Chelator Modifications on 68Ga-Labeled [Tyr3]Octreotide Conjugates 
Purpose
Somatostatin receptors (SSTR) have been reported as promising targets for imaging agents for cancer. Recently, 68Ga-DOTATOC-based PET imaging has been used successfully for diagnosis and management of SSTR-expressing tumors. The purpose of this study was to evaluate the influence of chelator modifications and charge on 68Ga-labeled peptide conjugates.
Procedures
We have synthesized a series of [Tyr3]octreotide conjugates that consisted of different NOTA-based chelators with two to five carboxylate moieties, and compared our results with 68Ga-DOTATOC in both in vitro and in vivo studies.
Results
With the exception of 68Ga-1 (three carboxylates), the increased number of carboxylates on the NOTA-based chelators resulted in a reduced binding affinity and internalization. Additionally, the tumor uptake for 68Ga-2 (four carboxylates) and 68Ga-3 (five carboxylates) was reduced compared to that of 68Ga-DOTATOC (three carboxylates) and 68Ga-NO2ATOC (two carboxylates) and 68Ga-1 (three carboxylates) at 2 h p.i. suggesting the presence of an optimal charge for this compound.
Conclusions
Chelator modifications can lead to the altered pharmacokinetics. These results may impact further design considerations for peptide-based imaging agents.
doi:10.1007/s11307-013-0627-x
PMCID: PMC4329983  PMID: 23529373
68Ga; Somatostatin receptor; [Tyr3]octreotide; Positron emission tomography; Peptide
22.  Combined PET/MR: The Real Work Has Just Started. Summary Report of the Third International Workshop on PET/MR Imaging; February 17–21, 2014, Tübingen, Germany 
Molecular Imaging and Biology  2015;17(3):297-312.
This paper summarises the proceedings and discussions at the third annual workshop held in Tübingen, Germany, dedicated to the advancement of the technical, scientific and clinical applications of combined PET/MRI systems in humans. Two days of basic scientific and technical instructions with “hands-on” tutorials were followed by 3 days of invited presentations from active researchers in this and associated fields augmented by round-table discussions and dialogue boards with specific themes. These included the use of PET/MRI in paediatric oncology and in adult neurology, oncology and cardiology, the development of multi-parametric analyses, and efforts to standardise PET/MRI examinations to allow pooling of data for evaluating the technology. A poll taken on the final day demonstrated that over 50 % of those present felt that while PET/MRI technology underwent an inevitable slump after its much-anticipated initial launch, it was now entering a period of slow, progressive development, with new key applications emerging. In particular, researchers are focusing on exploiting the complementary nature of the physiological (PET) and biochemical (MRI/MRS) data within the morphological framework (MRI) that these devices can provide. Much of the discussion was summed up on the final day when one speaker commented on the state of PET/MRI: “the real work has just started”.
doi:10.1007/s11307-014-0818-0
PMCID: PMC4422837  PMID: 25672749
Hybrid imaging; Molecular imaging; PET/CT; PET/MRI; PET; MRI; Quantification; Attenuation correction; Oncology; Paediatric oncology; Neurology; Cardiology
23.  IND-Directed Safety and Biodistribution Study of Intravenously Injected Cetuximab-IRDye800 in Cynomolgus Macaques 
Purpose
The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states, however, the toxicity of the bioconjugate has not been assessed in non-human primates.
Procedures
To this end, the in vivo toxicity and pharmacokinetics of IRDye800 conjugated to cetuximab (cetuximab-IRDye800; 21 mg/kg; equivalent to 250 mg/m2 human dose) was assessed in male cynomolgus monkeysover15 days following intravenous injection and compared with an unlabeled cetuximab-dosed control group.
Results
Cetuximab-IRDye800 was well tolerated. There were no infusion reactions, adverse clinical signs, mortality, weight loss, or clinical histopathology findings. The plasma half-life for the cetuximab-IRDye800 and cetuximab groups were equivalent (2.5 days). The total recovered cetuximab-IRDye800 in all tissues at study termination was estimated to be 12% of the total dose. Both cetuximab-IRDye800 and cetuximab groups showed increased QTc after dosing. The QTc for the cetuximab-dosed group returned to baseline by day 15, while the QTc of the cetuximab-IRDye800 remained elevated compared to baseline.
Conclusion
IRDye800 in low molar ratios does not significantly impact cetuximab half-life or result in organ toxicity. These studies support careful cardiac monitoring (ECG) for human studies using fluorescent dyes.
doi:10.1007/s11307-014-0773-9
PMCID: PMC4318248  PMID: 25080323
cetuximab; IRDye800; toxicity; macaques; pharmacokinetics
24.  [No title available] 
PMCID: PMC3947091  PMID: 23918654
25.  Utility of 18FLT-PET to Assess Treatment Response in Trastuzumab-resistant and Sensitive HER2-overexpressingHuman Breast Cancer Xenografts 
Purpose
Evaluate 3’-deoxy-3’-[18F]-fluorothymidine (18FLT) PET as an early marker of trastuzumab response in HER2-overexpressing xenografts.
Procedures
Tumor-to-muscle ratios were compared between both trastuzumab-sensitive and resistant cohorts prior to and after one and two treatments.
Results
A significant difference (P=0.03) was observed between treated and control trastuzumab-sensitive xenografts after one treatment, which preceded between-group differences in tumor volume. Reduced Ki67 (P=0.02) and thymidine kinase 1 (TK1) (P=0.35) immunoreactivity was observed in the treated xenografts. No significant differences in volume, tumor-to-muscle ratio, or immunoreactivity were observed between treated and control trastuzumab-resistant cohorts. A significant difference (P=0.02) in tumor-to-muscle ratio was observed between trastuzumab-sensitive and resistant cohorts after two treatments; however, tumor volumes were also different (P=0.04). Ki67 (P=0.04) and TK1 (P=0.24) immunoreactivity was ~50% less in trastuzumab-sensitive xenografts..
Conclusions
18FLT-PET provided early response assessment in trastuzumab-sensitive xenografts, but only differentiated between trastuzumab-resistant and sensitive xenografts concurrent with differences in tumor size.
doi:10.1007/s11307-014-0770-z
PMCID: PMC4311727  PMID: 25034624
18FLT-PET; assessing treatment response; HER2+ xenografts; breast cancer; trastuzumab

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