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26.  Development of a peptide by phage display for SPECT imaging of resistance-susceptible breast cancer 
Personalized medicine is at the forefront of cancer diagnosis and therapy. Molecularly targeted therapies such as trastuzumab and tamoxifen have enhanced prognosis of patients with cancers expressing ERBB2 and the estrogen receptor, respectively. One obstacle to targeted therapy is the development of resistance. A targeted peptide that could distinguish resistance-susceptible cancer would aid in treatment. BT-474 human breast cancer cells can be resistant to both tamoxifen and trastuzumab, and may serve as a model for malignancies in which targeted therapy may not work. Bacteriophage (phage) display is a combinatorial technology that has been used to isolate peptides that target a specific cancer subtype. It was hypothesized that in vivo phage display could be used to select a peptide for SPECT imaging of BT-474 human breast cancer xenografts. A phage library displaying random 15 amino acid peptides was subjected to four rounds of selection, after which 14 clones were analyzed for BT-474 binding and specificity. One phage clone, 51, demonstrated superior binding and specificity, and the displayed peptide was synthesized for in vitro characterization. Peptide 51 bound specifically to BT-474 cells with an EC50 = 2.33 µM and was synthesized as a DOTA-conjugated peptide and radiolabeled with 111In for in vitro and in vivo analysis. The radiolabeled peptide exhibited an IC50 = 16.1 nM to BT-474 cells and its biodistribution and SPECT imaging in BT-474 xenografted mice was analyzed. Although tumor uptake was moderate at 0.11% ID/g, SPECT imaging revealed a distinct tumor vasculature binding pattern. It was discovered that peptide 51 had an identical 5 amino acid N-terminal sequence to a peptide, V1, which bound to Nrp1, a tumor vasculature protein. Peptide 51 and V1 were examined for binding to target cells, and 51 bound both target and endothelial cells, while V1 only bound endothelial cells. Truncated versions of 51 did not bind BT-474 cells, demonstrating that the targeting ability of 51 was independent of the homologous V1 sequence. These results demonstrate that in vivo phage display can effectively identify a peptide that specifically targets a breast cancer cell line that is susceptible to targeted therapy resistance.
PMCID: PMC4138138  PMID: 25143862
Peptide; phage display; molecular imaging; breast cancer
27.  Feasibility of simultaneous PET/MR in diet-induced atherosclerotic minipig: a pilot study for translational imaging 
Novel hybrid 18-fluoro-deoxy-D-glucose (18F-FDG) based positron emission tomography (PET) and magnetic resonance imaging (MRI) has shown promise for characterization of atherosclerotic plaques clinically. The purpose of this study was to evaluate the method in a pre-clinical model of diet-induced atherosclerosis, based on the Göttingen minipig. Using 18F-FDG PET/MRI the goal was to develop and create a new imaging method in an in vivo animal model for translational studies of atherosclerosis. We used a strategy of multisequence MRI for optimal anatomical imaging of the abdominal aortas of the pigs (n=4): T1-weighted turbo spin-echo (T1-TSE), T2-weighted turbo spin-echo (T2-TSE) and proton density imaging with and without fat saturation. 18F-FDG PET emission data were collected from a single bed position of the abdominal aorta in 3D mode for either 10 (n=4) or 10 and 20 minutes (n=2) to measure glycolysis as given by standardized uptake values (SUV). Ex vivo en face evaluation of aortas from an atherosclerotic animal illustrated plaque distribution macroscopically, compared to a lean control animal. Although T2-TSE weighted imaging was most consistent, no one MRI sequence was preferable and superior to another for visualization and identification of the abdominal aorta. We found poor correlation between SUVs obtained from 10 and 20 minutes of reconstructed PET emission data. This can most likely be ascribed to intestinal movement. In conclusion multisequence MRI is recommended for optimal imaging of the abdominal aorta using MRI. Furthermore we found that 10 minutes of PET emission data seems adequate. This is the first study to demonstrate that the method of 18F-FDG PET/MRI is feasible in minipig models of atherosclerosis, and therefore relevant in larger prospective studies. Perspectives of the method include correlation to e.g. aortic immunohistochemistry findings and a range of genomic and proteomic analyses.
PMCID: PMC4138139  PMID: 25143863
Atherosclerosis; novel model; Göttingen minipig; positron emission tomography; magnetic resonance imaging
28.  A pilot study in epilepsy patients using simultaneous PET/MR 
Integrated PET/MR with simultaneous acquisition may improve the identification of pathologic findings in patients. This pilot study evaluated metabolic activity differences between epilepsy patients and healthy controls and directly correlated FDG uptake with MR regional abnormality. Epilepsy patients (n=11) and controls (n=6) were imaged on a whole-body simultaneous PET/MR scanner. After FDG injection, simultaneous images were acquired for 60 minutes. Statistical analyses on SUV values (over 117 brain regions, including left and right, for 96 cortical and 21 subcortical regions) derived from three normalization methods, by individual subject’s mean cortical, white matter or global brain, were compared between groups. The asymmetry was compared. T2, T1 and PET co-registered images were also used for lesion detection and correlation of PET and MR regional abnormality. Left and right postcentral gyri were found to be consistently hypermetabolic regions, while right temporal pole and planum polare were consistently hypometabolic regions by all three normalization methods. Using the asymmetry index (AI > 10% or SUV ratios > 1.2), more metabolic asymmetry regions were detected in patients than in controls, with 96.2% agreement. The presence of hippocampal abnormalities or cortical tubers detected via T2 FLAIR in patients correlated well with the hypometabolism detected via FDG-PET. Our results showed specific patterns of metabolic abnormality and asymmetry over 117 brain regions in epilepsy patients, as compared to controls, suggest that simultaneous PET/MR imaging provides a useful tool to help understand etiopathogenesis and localize seizure foci.
PMCID: PMC4138140  PMID: 25143864
Epilepsy; simultaneous PET/MR; FDG; asymmetry; hypermetabolism; hypometabolism
29.  Clinical impact of FDG-PET/CT on colorectal cancer staging and treatment strategy 
FDG-PET/CT is rarely used for initial staging of patients with colorectal cancer (CRC). Surgical resection of primary tumor and isolated metastases may result in long-term survival or presumed cure, whereas disseminated disease contraindicates operation. We analyzed a retrospective material to elucidate the potential value of FDG-PET/CT for staging of CRC. Data were retrieved from 67 consecutive patients (24-84 years) with histopathologically proven CRC who had undergone FDG-PET/CT in addition to conventional imaging for initial staging. Treatment plans before and after FDG-PET/CT were compared and patients divided as follows: (A) Patients with a change in therapy following FDG-PET/CT and (B) Patients without a change following FDG-PET/CT. Sixty-two patients had colon and five had rectal cancer. Of these, 20 (30%; CI 20.2-41.7) belonged to group A, whereas 47 (70%; CI 58.3-79.8) fell in group B. In conclusion, FDG-PET/CT changed treatment plan in 30% of cases. In ⅓ of these there was either a change from intended curative to palliative therapy or vice versa, while in the remaining ⅔ the pattern was more mixed. Thus, even in a retrospective routine material there were substantial changes in management strategy following FDG-PET/CT for staging in CRC.
PMCID: PMC4138141  PMID: 25143865
FDG-PET/CT; colorectal cancer; clinical impact; treatment strategy
30.  Initial in vivo PET imaging of 5-HT1A receptors with 3-[18F]mefway 
4-trans-[18F]Mefway is a PET radiotracer with high affinity for 5-HT1A receptors. Our preliminary work indicated the positional isomer, 3-[18F]mefway, would be suitable for PET imaging of 5-HT1A receptors. We now compare the in vivo behaviour of 3-mefway with 4-mefway to evaluate 3-[18F]mefway as a potential 5-HT1A PET radiotracer. Two male rhesus macaques were given bolus injections of both 3- and 4-trans-[18F]mefway in separate experiments. 90 minute dynamic PET scans were acquired. TACs were extracted in the mesial temporal lobe (MTL) and caudal anterior cingulate gyrus (cACg). The cerebellum (CB) was used as a reference region. In vivo behavior of the radiotracers in the CB was compared based upon the ratio of normalized PET uptake for 3- and 4-trans-[18F]mefway. Specific binding was compared by examining MTL/CB and cACg/CB ratios. The subject-averaged ratio of 3-[18F]mefway to 4-trans-[18F]mefway in the cerebellum was 0.96 for 60-90 minutes. MTL/CB reached plateaus of ~2.7 and ~6 by 40 minutes and 90 minutes for 3- and 4-trans-[18F]mefway, respectively. cACg/CB reached plateaus of ~2.5 and ~6 by 40 minutes and 70 minutes for 3- and 4-trans-[18F]mefway, respectively. The short pseudoequilibration times and sufficient uptake of 3-[18F]mefway may be useful in studies requiring short scan times. Furthermore, the similar nondisplaceable clearance in the CB to 4-trans-[18F]mefway suggests the lower BPND of 3-[18F]mefway is due to a lower affinity. The lower affinity of 3-[18F]mefway may make it useful for measuring changes in endogenous 5-HT levels, however, this remains to be ascertained.
PMCID: PMC4138142  PMID: 25143866
5-HT1A; PET; serotonin; mefway
31.  Peptide targeted high-resolution molecular imaging of prostate cancer with MRI 
Non-invasive accurate detection of prostate cancer is critical for clinical management of the disease. Molecular MRI has a potential for accurate detection of prostate cancer with high spatial resolution. Fibronectin is a hallmark of epithelial-mesenchymal transition occurred in aggressive prostate cancer and highly expressed in malignant tumors. A pentapeptide CREKA targeted contrast agent CREKA-dL-(DOTA-Gd)4 was synthesized and evaluated to target fibrin-fibronectin complexes in tumor extracellular matrix for molecular MRI of prostate cancer. The contrast agent was synthesized by solid-phase peptide synthesis. The T1 relaxivity of CREKA-(DOTA-Gd)4 at 1.5 T was 33.2 mM-1s-1 per molecule (8.3 per Gd). The fluorescence imaging showed that CREKA specifically bound to orthotopic PC3 prostate tumor in athymic nude mice. Strong enhancement was observed in the tumor tissue injected with CREKA-(DOTA-Gd)4 in the first 5 minutes post-injection before MR signal became visible in the bladder at a low dose of 0.03 mmol-Gd/kg. The targeted contrast agent exhibited minimal Gd retention in the main organs and tissues 2 days after injection. The peptide targeted contrast agent CREKA-(DOTA-Gd)4 is promising for high-resolution molecular MRI of prostate cancer.
PMCID: PMC4171839  PMID: 25250202
Molecular imaging; MRI; prostate cancer; peptide; targeted contrast agent
32.  Relationship between uptake of a radioiodinated quinazoline derivative and radiosensitivity in non-small cell lung cancer 
The aim of this study was to determine whether the uptake of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3’-iodophenoxy) quinazoline ([125I]PYK) could predict the response of non-small cell lung cancer (NSCLC) cells to radiotherapy in vitro. Four NSCLC cell lines, PC9, HCC827, A549, and H1975 were used. Cells were irradiated with doses ranging from 2 Gy to 8 Gy and/or exposed to 1 μM gefitinib. The effects of radiation and gefitinib were assessed by the CCK-8 assay and confirmed by reverse transcription-polymerase chain reaction and immunoflorescence microscopy. The uptake of [125I]PYK was determined by incubating cells with a tracer. The cell cycle was assessed by flow cytometry. The expression of EGFR was measured by western blotting. The results obtained revealed that the uptake of [125I]PYK was higher in PC9 and HCC827 cells than in A549 and H1975 cells. PC9 cells and HCC827 cells were also more radiosensitive than A549 and H1975 cells. The gefitinib pretreatment reduced the S phase fraction and enhanced radiation effects in PC9 and HCC827 cells. These results indicate that the uptake of [125I]PYK is related to the effects of radiation in NSCLC cells. Radioiodinated PYK may be useful in predicting the response of NSCLC in patients to radiotherapy.
PMCID: PMC4074495  PMID: 24982815
[125I]PYK; irradiation; gefitinib; EGFR; NSCLC
33.  Cyclotron production of 68Ga via the 68Zn(p,n)68Ga reaction in aqueous solution 
The objective of the present work is to extend the applicability of the solution target approach to the production of 68Ga using a low energy cyclotron. Since the developed method does not require solid target infrastructure, it offers a convenient alternative to 68Ge/68Ga generators for the routine production of 68Ga. A new solution target with enhanced heat exchange capacity was designed and utilized with dual foils of Al (0.20 mm) and Havar (0.038 mm) separated by helium cooling to degrade the proton energy to ~14 MeV. The water-cooled solution target insert was made of Ta and its solution holding capacity (1.6 mL) was reduced to enhance heat transfer. An isotopically enriched (99.23%) 1.7 M solution of 68Zn nitrate in 0.2 N nitric acid was utilized in a closed target system. After a 30 min irradiation at 20 μA, the target solution was unloaded to a receiving vessel and the target was rinsed with 1.6 mL water, which was combined with the target solution. An automated module was used to pass the solution through a cation-exchange column (AG-50W-X8, 200-400 mesh, hydrogen form) which efficiently trapped zinc and gallium isotopes. 68Zn was subsequently eluted with 30 mL of 0.5 N HBr formulated in 80% acetone without any measurable loss of 68Ga. 68Ga was eluted with 7 mL of 3 N HCl solution with 92-96% elution efficiency. The radionuclidic purity was determined using an HPGe detector. Additionally, ICP-MS was employed to analyze for non-radioactive metal contaminants. The product yield was 192.5 ± 11.0 MBq/μ·h decay-corrected to EOB with a total processing time of 60-80 min. The radionuclidic purity of 68Ga was found to be >99.9%, with the predominant contaminant being 67Ga. The ICP-MS analysis showed small quantities of Ga, Fe, Cu, Ni and Zn in the final product, with 68Ga specific activity of 5.20-6.27 GBq/μg. Depending upon the user requirements, 68Ga production yield can be further enhanced by increasing the 68Zn concentration in the target solution and extending the irradiation time. In summary, a simple and efficient method of 68Ga production was developed using low energy cyclotron and a solution target. The developed methodology offers a cost-effective alternative to the 68Ge/68Ga generators for the production of 68Ga.
PMCID: PMC4074496  PMID: 24982816
68Ga; cyclotron targetry; solution target
34.  Preclinical evaluation of 111In-DTPA-INCA-X anti-Ku70/Ku80 monoclonal antibody in prostate cancer 
The aim of this investigation was to assess the Ku70/Ku80 complex as a potential target for antibody imaging of prostate cancer. We evaluated the in vivo and ex vivo tumor targeting and biodistribution of the 111In-labeled human internalizing antibody, INCA-X (111In-DTPA-INCA-X antibody), in NMRI-nude mice bearing human PC-3, PC-3M-Lu2 or DU145 xenografts. DTPA-conjugated, non-labeled antibody was pre-administered at different time-points followed by a single intravenous injection of 111In-DTPA-INCA-X. At 48, 72 and 96 h post-injection, tissues were harvested, and the antibody distribution was determined by measuring radioactivity. Preclinical SPECT/CT imaging of mice with and without the predose was performed at 48 hours post-injection of labeled DTPA-INCA-X. Biodistribution of the labeled antibody showed enriched activity in tumor, spleen and liver. Animals pre-administered with DTPA-INCA-X showed increased tumor uptake and blood content of 111In-DTPA-INCA-X with reduced splenic and liver uptake. The in vitro and in vivo data presented show that the 111In-labeled INCA-X antibody is internalized into prostate cancer cells and by pre-administering non-labeled DTPA-INCA-X, we were able to significantly reduce the off target binding and increase the 111In-DTPA-INCA-X mAb uptake in PC-3, PC-3M-Lu2 and DU145 xenografts. The results are encouraging and identifying the Ku70/Ku80 antigen as a target is worth further investigation for functional imaging of prostate cancer.
PMCID: PMC4074497  PMID: 24982817
Ku80/Ku80; INCA-X monoclonal antibody; prostate cancer; tumor targeting; preclinical SPECT/CT
35.  Targeting histone deacetylase in lung cancer for early diagnosis: 18F-FAHA PET/CT imaging of NNK-treated A/J mice model 
Elevated levels of histone deacetylases (HDACs) have been indicated in the development of some cancers. HDAC has been imaged using 18F-FAHA and may serve as a marker to study epigenetics. We report evaluation of 18F-FAHA as a probe in the early diagnosis of lung cancer using 18F-FAHA PET/CT studies of A/J mice treated with NNK. 18F-FAHA radiosynthesis was carried out in specific activity of ~2 Ci/μmol. A/J mice were divided into 2 groups: 1. Controls; 2. NNK treatment group with NNK (100 mg/kg, ip, weekly for 4 wks). Mice were injected 100-200 μCi i.v. 18F-FAHA and then scanned in Inveon PET/CT under anesthesia using 2.0% isoflurane. Midbrain, cerebellum and brainstem uptake of 18F-FAHA was displaced by the known HDAC inhibitor, suberanilohydroxamic acid (SAHA) with less than 10% activity remaining. CT revealed presence of lung nodules in 8 to 10-month old NNK mice while control mice were free of tumors. Little uptake of 18F-FAHA was observed in the control mice lungs while significant 18F-FAHA uptake occurred in the lungs of NNK-treated mice with tumor/nontumor >2.0. Ex vivo scans of the excised NNK and control mice lungs confirmed presence of extensive amounts of lung nodules seen by CT and confirmed by 18F-FAHA in the NNK mice with tumor/nontumor >6.0. Our preliminary imaging studies with A/J mice lung cancer model suggest 18F-FAHA PET may allow the study of epigenetic mechanisms involved in NNK-induced tumorigenesis in the lungs.
PMCID: PMC4074498  PMID: 24982818
Lung cancer; histone deacetylase; 18F-Nifene; 18F-FAHA; 18F-FDG; NNK; A/J mice; PET/CT
36.  Molecular imaging of integrin αvβ6 expression in living subjects 
Integrins, a family of cell adhesion molecules composed of α and β heterodimeric subunits, are involved in a wide range of cell-extracellular matrix and cell-cell interactions. The study of integrin family members as targets for molecular imaging and therapy has been generally limited with the exception of integrin αvβ3. vβ6, a member of the integrin family, is expressed at low or undetectable levels in normal tissues, but is widely upregulated during many pathological and physiological processes, especially cancer and fibrosis, making it a promising target for molecular imaging. Noninvasive and quantitative imaging of integrin vβ6 expression would be very useful for disease diagnosis, treatment monitoring, and prognosis assessment. Although various molecular probes have been developed for positron emission tomography and single-photon emission computed tomography imaging of integrin vβ6 expression in preclinical animal models, further research efforts are required to optimize integrin vβ6-targeting probes for future potential clinical applications in the fields of oncology and beyond.
PMCID: PMC4074499  PMID: 24982819
Molecular probe; noninvasive imaging; positron emission tomography (PET); single-photon emission computed tomography (SPECT); cancer; fibrosis; wound healing
37.  Variability in myocardial metabolism on serial tumor 18F-FDG PET/CT scans 
18F Fluorodeoxyglucose (FDG) positron emission tomography (PET) scans are performed routinely for oncologic patients. Myocardial uptake can vary among patients and between serial studies in the same patient. Our study aims to evaluate myocardial metabolism on staging FDG PET scans and to analyze factors influencing patterns of cardiac uptake, and their relevance. We analyzed retrospectively 100 PET-CT scans from 20 fasting lymphoma patients. Distribution of myocardial uptake was determined by visual assessment and the maximum standardized uptake value (SUVm) was calculated. Multiple variables were analyzed including: fasting length, cardiovascular risk factors, SUVm, and location of uptake. We found no correlation between fasting hours and cardiac uptake (p-value: 0.4786). There was a trend that showed less uptake in patients scanned in the afternoon versus the morning, although this was not statistically significant. The location of maximum uptake was unexpectedly variable in several patients and could not be ascertained to a specific cause. Interestingly, we found no correlation between cardiac risk factors and the amount of myocardial uptake. Myocardial FDG uptake is spatially and temporally heterogeneous. Differences in myocardial wall pattern and peak uptake exist and may not be explained by the length of fasting, gender, age or cardiac risk factors. This variability may occur in daily cardiac evaluations and affect interpretations of sarcoidosis and viability studies and should be further explored. A larger cohort study is necessary to confirm that our findings do not confer a higher cardiac risk profile to the cancer patient.
PMCID: PMC4074500  PMID: 24982820
Myocardial metabolism; cardiac FDG; fasting and FDG serial tumor PET; myocardial FDG heterogeneity
38.  Synthesis and evaluation of 2-18F-fluoro-5-iodo-3-[2-(S)-3,4-dehydropyrrolinylmethoxy]pyridine (18F-Niofene) as a potential imaging agent for nicotinic α4β2 receptors 
Nicotinic α4β2 acetylcholine receptors (nAChRs) have been implicated in various pathophysiologies including neurodegenerative diseases. Currently, 2-18F-A85380 (2-FA) and 5-123I-A85380 (5-IA) are used separately in human PET and SPECT studies respectively and require >4-6 hours of scanning. We have developed 2-fluoro-5-iodo-3-[2-(S)-3-dehydropyrrolinylmethoxy]pyridine (niofene) as a potential PET/SPECT imaging agent for nAChRs with an aim to have rapid binding kinetics similar to that of 18F-nifene used in PET studies. Niofene exhibited a 10-fold better in vitro binding affinity in rat brain than that of nicotine. The relative binding of niofene was similar to that of niodene and twice as better as that of nifene. In vitro autoradiography in rat brain slices alongside niodene indicated selective binding of niofene to regions consistent with α4β2 receptor distribution. Niofene, 10 nM, displaced >70% of 3H-cytisine bound to α4β2 receptors in rat brain slices. Radiolabeling of 18F-niofene was achieved in 10-15% radiochemical yield in high specific activities >2 Ci/μmol and showed rapid in vivo kinetics similar to that of 18F-nifene and 18F-nifrolene. In vivo PET in rats showed rapid uptake in the brain and selective localization in receptor regions such as the thalamus (TH). Pseudoequilibrium with 18F-niofene was achieved in 30-40 minutes, which is similar to that of 18F-nifene. Further evaluation of 18F-niofene as a potential PET imaging agent is underway. Future studies will be conducted to radiolabel niofene with iodine-123 for use in SPECT imaging.
PMCID: PMC4074501  PMID: 24982821
Nicotine; nifene; niodene; nifrolene; fluorine-18
39.  PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence  
Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls.
PMCID: PMC4074502  PMID: 24982822
Hypoxia; tumor imaging; PET; 18F-FDG; 18F-FMISO; 18F-FAZA; 64Cu-ATSM
40.  Quantitative 99mTc DTPA renal transplant scintigraphic parameters: assessment of interobserver agreement and correlation with graft pathologies 
Various 99mTc DTPA scintigraphic quantitative parameters for renal graft function assessment have been recommended, but none is universally accepted. In this study, 439 dynamic renal transplant scintigraphies (DRTS) were retrospectively analysed. In the first set of studies, four observers analysed the 47 random DRTS and interobserver agreement of eleven derived parameters was assessed. In the other set of studies, 181 instances of DRTS, performed on 127 recipients with renal biopsies within five days of each other were selected for correlation with pathology. Hilson’s Perfusion index (HI), ΔP, P:Pl, P:U & T10 were selected for this analysis. The pathologies were categorized into renal vascular compromise (RVC; n = 20), acute tubular necrosis (ATN; n = 40), vascular rejection (VR; n = 34), interstitial rejection (IR; n = 33), normal (NOR; n = 36) and unclassified pathologies (n = 18). A majority of the parameters showed good Intraclass correlation (ICC). HI differentiated well between grafts with RVC and the remainder of the study cohort, (p < 0.0001; AUC = 0.84); at a cut-off > 278, it had 84% sensitivity and 78% specificity (Likelihood ratio = 3.8). At < 278, it had 98% ‘negative’ predictive value for RVC. HI also showed reasonable association with VR (p = 0.02; AUC = 0.62) and IR (p = 0.009; AUC = 0.65). However, significant overlap of HI values between various subgroups was noted. Other parameters had good ICC but were not effective in differentiating graft pathologies. Of the measured parameters, only HI proved to be useful for the pathological assessment, particularly in the identification of vascular compromise. This parameter, however, has lower specificity in differentiating the other pathologies.
PMCID: PMC3999401  PMID: 24795835
Acute tubular necrosis; Hilson’s index; interobserver agreement; quantitative renal transplant DTPA scintigraphy; rejection; renal artery stenosis; renal graft
41.  PET/CT in the diagnosis of inflammatory bowel disease in pediatric patients: a review 
The literature on positron emission tomography and computed tomography using 18fluoro-deoxyglusose (FDG-PET/CT) in the diagnosis of pediatric inflammatory bowel disease (IBD) is presented. Only five papers representing independent studies were identified and included in this review. Of these, two studies dealt with both stand-alone FDG-PET and FDG-PET/CT, while three were about stand-alone FDG-PET only. No studies could be found that focused on FDG-PET/CT only. The five studies comprised analysis of a total 181 pediatric patients (0-18 years of age). They unanimously indicated that FDG-PET/CT is a versatile method with a diagnostic high sensitivity ranging from 70% to 97%. In conclusion, the pediatric literature on FGD-PET/CT’s role in the diagnosis of IBD is very limited. Prospective studies of well characterized populations are needed in order to validate this novel imaging modality in pediatric IBD.
PMCID: PMC3999402  PMID: 24795836
Inflammatory bowel disease; ulcerative colitis; Crohn’s disease; positron-emission tomography and computed tomography
42.  Relationship between pretreatment FDG-PET and diffusion-weighted MRI biomarkers in diffuse large B-cell lymphoma 
The purpose of this study was to determine the correlation between the 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm2) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson’s correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL.
PMCID: PMC3999403  PMID: 24795837
FDG-PET; diffusion-weighted MRI; standardized uptake value; apparent diffusion coefficient; diffuse large B-cell lymphoma
43.  Cognitive reserve and clinical expression of Alzheimer’s disease: evidence and implications for brain PET imaging 
Cognitive reserve (CR) refers to the hypothesized capacity of an adult brain to cope with brain damage in order to minimize symptomatology. The present review is focused on the contribution of brain PET in the understanding of the influence of CR on the disassociation between cognition and degree of Alzheimer’s disease (AD) pathology. Theories for the explanation CR-related mechanism as well as PET imaging evidence for the existence of CR are described. Moreover functional imaging studies investigating specific networks for CR both in healthy subjects and AD patients are discussed. Finally implications for amyloid PET imaging are presented.
PMCID: PMC3999404  PMID: 24795838
Brain FDG PET; Alzheimer’s disease; cognitive reserve; amyloid PET; mild cognitive impairment
44.  Automated synthesis and dosimetry of 6-deoxy-6-[18F]fluoro-D-fructose (6-[18F]FDF): a radiotracer for imaging of GLUT5 in breast cancer 
6-Deoxy-6-[18F]fluoro-D-fructose (6-[18F]FDF) is a promising PET radiotracer for imaging GLUT5 in breast cancer. The present work describes GMP synthesis of 6-[18F]FDF in an automated synthesis unit (ASU) and dosimetry calculations to determine radiation doses in humans. GMP synthesis and dosimetry calculations are important prerequisites for first-in-human clinical studies of 6-[18F]FDF. The radiochemical synthesis of 6-[18F]FDF was optimized and adapted to an automated synthesis process using a Tracerlab FXFN ASU (GE Healthcare). Starting from 30 GBq of cyclotron-produced n.c.a. [18F]fluoride, 2.9 ± 0.1 GBq of 6-[18F]FDF could be prepared within 50 min including HPLC purification resulting in an overall decay-corrected radiochemical yield of 14 ± 3% (n = 11). Radiochemical purity exceeded 95%, and the specific activity was greater than 5.1 GBq/μmol. Sprague-Dawley rats were used for biodistribution experiments, and dynamic and static small animal PET experiments. Biodistribution studies served as basis for allometric extrapolation to the standard man anatomic model and normal organ-absorbed dose calculations using OLINDA/EXM software. The calculated human effective dose for 6-[18F]FDF was 0.0089 mSv/MBq. Highest organ doses with a dose equivalent of 0.0315 mSv/MBq in a humans were found in bone. Injection of 370 MBq (10 mCi) of 6-[18F]FDF results in an effective whole body radiation dose of 3.3 mSv in humans, a value comparable to that of other 18F-labeled PET radiopharmaceuticals. The optimized automated synthesis under GMP conditions, the good radiochemical yield and the favorable human radiation dosimetry estimates support application of 6-[18F]FDF in clinical trials for molecular imaging of GLUT5 in breast cancer patients.
PMCID: PMC3999405  PMID: 24795839
Positron emission tomography; automated synthesis; dosimetry; 6-[18F]FDF; GLUT5
45.  PET brain kinetics studies of 11C-ITMM and 11C-ITDM,radioprobes for metabotropic glutamate receptor type 1, in a nonhuman primate 
The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed 11C-labeled PET probes 11C-ITMM and 11C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared 11C-ITMM and 11C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with 11C-ITDM than with 11C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm-3 for 11C-ITMM and 3.6 mL∙cm-3 for 11C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of 11C-ITMM and 11C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that 11C-ITDM may be superior to 11C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with 11C-ITDM were higher than those of 11C-ITMM. Clinical studies of 11C-ITDM in humans will be necessary in the future.
PMCID: PMC3999406  PMID: 24795840
Central nervous system (CNS); positron emission tomography (PET); metabotropic glutamate receptor type 1 (mGluR1)
46.  Sexually immature male ERE-Luc reporter mice to assess low dose estrogen-like effects of CdCl2 versus dietary Cd 
CdCl2 salt is widely used in exposure oriented studies, while the biological exposure of Cadmium (Cd) occurs mostly through diet. Hence, we designed a in vivo imaging methodology with sexually immature male ERE-Luc reporter mice to test the estrogen-like (EL) effects of Cd as a natural component in wheat and flax bread based diets (containing 17.57 and 49.22 ug/kg Cd concentrations respectively) and CdCl2 per-oral dose of 1 ug/kg/bw/day. Total exposure of ingested and % bioaccumulation of Cd in selected organs were estimated as 547 ng (4.4%), 776 ng (0.3%) and 2131.8 ng (0.1%) corresponding to CdCl2, wheat and flax bread based diet treatments respectively. Cd from CdCl2 bioaccumulated more readily, despite the exposure of Cd is higher with bread based diets. Longitudinal in vivo imaging did not reveal significant changes in luciferase activity. White adipose tissue (WAT) and prostate were identified as novel target organs of Cd. Indeed, the rest of the observed EL effects, endogenous target gene expression and necropsy findings are not consistent to any particular organ or treatment. This implies that, the observed EL effects due to low doses of Cd (either from CdCl2 or dietary form) occur only as subtle changes at the molecular level, but inadequate to cause significant changes at the anatomo-pathological level during the 21 day exposure period. The study demonstrates the sensitivity of the methodology to assess EL effects of food embedded Cd and underlines the limitations of directly extrapolating the results of suspected chemicals in their pure form to dietary exposure scenarios.
PMCID: PMC3999407  PMID: 24795841
Reporter mice; in vivo imaging; estrogenicity; CdCl2; dietary Cd; bioavailability; endocrine disruptors
47.  Positron emission tomography imaging for vascular inflammation evaluation in elderly subjects with different risk factors for cardiovascular diseases 
This study was aimed to investigate the usefulness of 18F-FDG-PET to differentiate vascular inflammation and to determine the effect of rosuvastatin. Eight subjects were recruited and were divided according to their health status in three groups; 3 healthy subjects, 3 patients with hypercholesterolemia and 2 patients with stable angina pectoris. Hypercholesterolemic patients were submitted immediately after their recruitment to rosuvastatin treatment (20 mg/d). Two PET/CT measurements were made throughout the course of the study, one at baseline and the second 12 months later. Our results showed that the ratio of calcified arteries to total analyzed arteries segments were 23%, 36% and 44% for healthy, hypercholesterolemic and stable angina patients respectively. Healthy subjects present, at baseline, a high level of vascular inflammation as measured by 18F-FDG uptake in both calcified and non-calcified segments of the arteries. This vascular inflammation increases as a function of the cardiovascular risk factors. After the 12-month follow-up period, non-calcified arteries showed a significant increase of 18F-FDG uptake in both healthy, hypercholesterolemic and stable angina patients. However, the highest increase was noted for the healthy subjects; (50% increase, p<0.0001), while hypercholesterolemic patients under rosuvastatin showed only 25% increase of 18F-FDG uptake (p<0.0001). This study confirms the usefulness of 18F-FDG measurement to localize and quantify arterial inflammation in each artery segments and as a function of the CVD risk factors. Rosuvastatin may have a protective effect against arterial inflammation however; other studies with higher rosuvastatin doses (>20 mg/d) are needed to confirm this beneficial effect.
PMCID: PMC3999408  PMID: 24795842
Atherosclerosis; positron emission tomography; 18F-FDG; vascular inflammation; aging; rosuvastatin
48.  Bioorthogonal chemistry: implications for pretargeted nuclear (PET/SPECT) imaging and therapy 
Due to their rapid and highly selective nature, bioorthogonal chemistry reactions are attracting a significant amount of recent interest in the radiopharmaceutical community. Over the last few years, reactions of this type have found tremendous utility in the construction of new radiopharmaceuticals and as a method of bioconjugation. Furthermore, reports are beginning to emerge in which these reactions are also being applied in vivo to facilitate a novel pretargeting strategy for the imaging and therapy of cancer. The successful implementation of such an approach could lead to dramatic improvements in image quality, therapeutic index, and reduced radiation dose to non-target organs and tissues. This review will focus on the potential of various bioorthogonal chemistry reactions to be used successfully in such an approach.
PMCID: PMC3992206  PMID: 24753979
Pretargeting; bioorthogonal chemistry; molecular imaging; PET; SPECT; click chemistry
49.  Multiplexing SERS nanotags for the imaging of differentiated mouse embryonic stem cells (mESC) and detection of teratoma in vivo  
Herein, we report fifty four membered, a new set of novel NIR Raman reporters and CyRLA-572 has been selected to be the best among them considering the signal intensity and stability. This new reporter molecule is an excellent partner with our in house Raman reporters (Cy7LA and Cy7.5LA). These three NIR Raman reporters are adsorbed on the gold nanoparticles to obtain their corresponding unique SERS fingerprints in which three individual characteristic peaks are capable to multiplex among them. These multiplexed Raman reporters are applied to develop biocompatible and specific targeting SERS nanotags after tagging with specific antibodies. These multiplex targeted SERS nanotags are applied to detect three targeting receptors in differentiated mouse embryonic stem cells (mESCs) consisting three germ layers such as ectoderm, mesoderm and endoderm. After successful recognition of cells by SERS techniques, we detect simultaneously three germ layers in teratoma which is a monster tumor formed from mESC cells in animal xenograft model.
PMCID: PMC3992207  PMID: 24753980
Gold nanoparticles; multiplexing; teratoma; biocompatible; nanotags; in vivo; SERS; cell mapping; differentiated germ layers; mesoderm; endoderm; ectoderm
50.  Modeling and imaging cardiac sympathetic neurodegeneration in Parkinson’s disease 
Parkinson’s disease (PD) is currently recognized as a multisystem disorder affecting several components of the central and peripheral nervous system. This new understanding of PD helps explain the complexity of the patients’ symptoms while challenges researchers to identify new diagnostic and therapeutic strategies. Cardiac neurodegeneration and dysautonomia affect PD patients and are associated with orthostatic hypotension, fatigue, and abnormal control of electrical heart activity. They can seriously impact daily life of PD patients, as these symptoms do not respond to classical anti-parkinsonian medications and can be worsened by them. New diagnostic tools and therapies aiming to prevent cardiac neurodegeneration and dysautonomia are needed. In this manuscript we critically review the relationship between the cardiovascular and nervous system in normal and PD conditions, current animal models of cardiac dysautonomia and the application of molecular imaging methods to visualize cardiac neurodegeneration. Our goal is to highlight current progress in the development of tools to understand cardiac neurodegeneration and dysautonomia and monitor the effects of novel therapies aiming for global neuroprotection.
PMCID: PMC3992208  PMID: 24753981
Positron emission tomography; SPECT; 18F-FDA; 11C-MHED; cardiac dysautonomia; sympathetic nervous system; Parkinson’s disease

Results 26-50 (158)