共查询到11条相似文献,搜索用时 15 毫秒
1.
Shuanglong Liu Zhaofei Liu Kai Chen Yongjun Yan Petra Watzlowik Hans-Jürgen Wester Frederick T. Chin Xiaoyuan Chen 《Molecular imaging and biology》2010,12(5):530-538
Purpose
In vivo imaging of αvβ3 has important diagnostic and therapeutic applications. 18F-Galacto-arginine–glycine–aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin αvβ3 expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin αvβ3-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used 18F-galacto-RGD.Procedures
RGD monomers and dimers were coupled with galacto or PEG3 linkers, and labeled with 18F using 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP) or N-succinimidyl 4-18F-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model.Results
Starting with 18F-F?, the total reaction time for 18F-FP-SRGD2 and 18F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for 18F-FP-SRGD2 and 18F-FP-PRGD2 are 52?±?9% and 80?±?7% calculated from 18F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to 18F-galacto-RGD.Conclusion
Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin αvβ3 imaging.2.
Alexandra Andriu Julie Crockett Sergio Dall’Angelo Monica Piras Matteo Zanda Ian N. Fleming 《Molecular imaging and biology》2018,20(1):27-36
Purpose
Molecular imaging of αvβ3 integrin has exhibited real potential to guide the appropriate use of anti-angiogenic therapies. However, an incomplete understanding of the factors that influence binding of αvβ3 integrin-specific radiotracers currently limits their use for assessing response to therapy in cancer patients. This study identifies two fundamental factors that modulate uptake of these radiotracers.ProceduresExperiments were performed in prostate cancer (PC3) and glioblastoma (U87MG) cells, which differentially express αvβ3 integrin. αvβ3 integrin-specific radiotracers were used to investigate the effect of manipulating αvβ3 integrin expression or activation in cellular binding assays. β3 integrin and αvβ3 integrin expression were measured by western blotting and flow cytometry, respectively. The effect of select pharmacological inhibitors on αvβ3 integrin activation and expression was also determined.Results
Radiotracer binding was proportional to αvβ3 integrin expression when it was decreased (β3 knock-down cells) or increased, either using pharmacological inhibitors of cell signalling or by culturing cells for different times. Studies with both small molecule and arginine–glycine–aspartic acid (RGD)-based radiotracers revealed increased radiotracer binding after activation of αvβ3 integrin with Mn2+ or talin head domain. Moreover, inhibition of fundamental signalling pathways (mitogen-activated protein kinase kinase (MEK), Src and VEGFR2) decreased radiotracer binding, reflecting reduced αvβ3 integrin activity.Conclusion
Binding of small molecule ligands and radiolabelled RGD peptides is modulated by expression and activation status of αvβ3 integrin. αvβ3 integrin-specific radiotracers can provide otherwise inaccessible information of the effect of signalling pathways on αvβ3 integrin. This has significant implications for assessing response to anti-angiogenic therapies in clinical studies.3.
Yared Tekabe Qing Li Geping Zhang Jordan Johnson Ann Marie Schmidt Marina Backer Joseph Backer Lynne L. Johnson 《Molecular imaging and biology》2018,20(6):963-972
Purpose
To compare targeted imaging of vascular endothelial growth factor (VEGF) receptors vs. αvβ3 integrins in a mouse hindlimb ischemia model of peripheral artery disease.Procedures
Male wild-type (WT) C57BL/6 mice (8- to 10-week old) (n?=?24) underwent left femoral artery ligation. The right leg served as control. Five days later, mice were injected with either VEGF receptor targeting [99mTc]DOTA-PEG-scVEGF ([99mTc]scV) (n?=?8) or with αvβ3-targeting tracer [99mTc]HYNIC-cycloRGD ([99mTc]RGD) (n?=?8) and underwent single photon emission computed tomography (SPECT) x-ray computed tomography imaging. To assess non-specific [99mTc]scV uptake, six additional mice received a mixture of [99mTc]scV and 30-fold excess of targeting protein, scVEGF. Tracer uptake as %ID was measured using volumetric regions encompassing the hindlimb muscles and as %ID/g from harvested limb muscles. Double and triple immunofluorescent analysis on tissue sections established localization of αvβ3, VEGFR-1, VEGFR-2, as well as certain cell lineage markers.Results
Tracer uptake, as %ID/g, was higher in ligated limbs of mice injected with [99mTc]scV compared to ligated hindlimbs in mice injected with [99mTc]RGD (p?=?0.02). The ratio of tracer uptake for ligated/control hindlimb was borderline higher for [99mTc]scV than for [99mTc]RGD (p?=?0.06). Immunofluorescent analysis showed higher prevalence of VEGFR-1, VEGFR-2, and αvβ3, in damaged vs. undamaged hindlimb tissue, but with little co-localization of these markers. Double immunofluorescent staining showed partial co-localization of VEGFR-1, VEGFR-2, and αvβ3, with endothelial cell marker FVIII, but not with CD31. Immunostaining for VEGFR-1 and VEGFR-2 additionally co-localized with lineage markers for endothelial progenitor cell and monocytes/macrophages, with a more diverse pattern of co-localization for VEGFR-2.Conclusion
In a mouse hindlimb ischemia model of peripheral artery disease, [99mTc]scV SPECT tracer-targeting VEGF receptors showed a more robust signal than [99mTc]RGD tracer-targeting αvβ3. Immunofluorescent analysis suggests that uptake of [99mTc]scV and [99mTc]RGD in damaged tissue is due to non-overlapping cell populations and reflects different dynamic processes and that enhanced uptake of [99mTc]scV may be due to the presence of VEGF receptors on additional cell types.4.
Zhaofei Liu Bing Jia Huiyun Zhao Xiaoyuan Chen Fan Wang 《Molecular imaging and biology》2011,13(1):112-120
Purpose
The cell adhesion molecule integrin αvβ3 is an important player in the process of tumor angiogenesis and metastasis. Abegrin™, a fully humanized anti-integrin αvβ3 monoclonal antibody, was currently in clinical trials for cancer therapy. Herein, we labeled Abegrin™ with 111In, evaluated the in vitro and in vivo characteristics, and investigated whether the expression of integrin αvβ3 in tumors could be imaged with 111In-labeled Abegrin™. 相似文献5.
Zhenying Chen Fangmeng Fu Fang Li Zhaohui Zhu Yinghong Yang Xiangjin Chen Bing Jia Shan Zheng Chao Huang Weibing Miao 《Molecular imaging and biology》2018,20(5):846-856
Purpose
This study aimed to investigate the value of 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid ([99mTc]3PRGD2) imaging in diagnosis and staging of breast cancer compared with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) imaging, and to explore the expression of integrin αvβ3 in tumor vascular endothelial cells.Procedures
Forty-two women with suspected breast cancer underwent both [99mTc]3PRGD2 imaging and [18F]FDG imaging. Visual analysis was used to assess primary breast lesion, axillary lymph node, and distant metastasis. The tumor-blood (T/B) ratios from [99mTc]3PRGD2 imaging and the maximum standardized uptake value (SUVmax) from [18F]FDG imaging were analyzed for breast lesions. Integrin αvβ3 was analyzed through immunohistochemistry.Results
Forty-five breast lesions were found (malignant, n?=?38; benign, n?=?7). The sensitivity, specificity, and accuracy of [99mTc]3PRGD2 and [18F]FDG imaging in visual analysis for the breast lesion were 97.4, 87.5, and 95.6 % and 97.4, 71.4, and 93.3 %, respectively (P?>?0.05). For semi-quantitative analysis, no significant difference of the area under the curves (AUC) was found in the imaging using the two radiopharmaceuticals (0.880 and 0.955; Z?=?0.88, P?>?0.05). The sensitivity, specificity, and accuracy for axillary lymph node metastasis with [99mTc]3PRGD2 and [18F]FDG were 78.05, 99.36, and 94.92 % and 85.37, 98.72, and 95.64 %, respectively (P?>?0.05). Nine patients with distant metastases were all detected with the two radiopharmaceuticals. The expression of integrin αvβ3 was correlated with [99mTc]3PRGD2 uptake (r?=?0.582, P?=?0.001), which were significantly higher in the HER2-positive and stage III–IV patients (P?<?0.05).Conclusions
The prospective study demonstrated that [99mTc]3PRGD2 imaging seems to be valuable for diagnosis of breast cancer and its staging. It may be less sensitive for detecting small lymph node metastatic lesions when compared with [18F]FDG imaging. Integrin αvβ3 in tumor microvessels was associated with the breast cancer subtype and its staging.6.
Bing Jia Zhaofei Liu Zhaohui Zhu Jiyun Shi Xiaona Jin Huiyun Zhao Fang Li Shuang Liu Fan Wang 《Molecular imaging and biology》2011,13(4):730-736
Purpose
99mTc-3PRGD2 is a 99mTc-labeled dimeric cyclic RGD peptide with increased receptor binding affinity and improved kinetics for in vivo imaging of integrin αvβ3 expression in nude mouse model. To accelerate its clinical translation, we reported here the evaluation of the kit-formulated 99mTc-3PRGD2 in healthy cynomolgus primates for its blood clearance kinetics, biodistribution, and radiation dosimetry. 相似文献7.
Lina Y. Hu Nadine Bauer Leah M. Knight Zibo Li Shuanglong Liu Carolyn J. Anderson Peter S. Conti Julie L. Sutcliffe 《Molecular imaging and biology》2014,16(4):567-577
Purpose
The integrin αvβ6 is overexpressed in a variety of aggressive cancers and serves as a prognosis marker. This study describes the conjugation, radiolabeling, and in vitro and in vivo evaluation of four chelators to determine the best candidate for 64Cu radiolabeling of A20FMDV2, an αvβ6 targeting peptide.Procedures
Four chelators were conjugated onto PEG28-A20FMDV2 (1): 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and 4,4′-((3,6,10,13,16,19-hexazazbicyclo[6.6.6]ico-sane-1,8-diylbis(aza-nediyl))bis(methylene)dibenzoic acid (BaBaSar). All peptides were radiolabeled with 64Cu in ammonium acetate buffer at pH 6 and formulated to pH 7.2 in PBS for use. The radiotracers were evaluated using in vitro cell binding and internalization assays and serum stability assays. In vivo studies conducted include blocking, biodistribution, and small animal PET imaging. Autoradiography and histology were also conducted.Results
All radiotracers were radiolabeled in good radiochemical purity (>95 %) under mild conditions (37–50 °C for 15 min) with high specific activity (0.58–0.60 Ci/μmol). All radiotracers demonstrated αvβ6-directed cell binding (>46 %) with similar internalization levels (>23 %). The radiotracers 64Cu-CB-TE1A1P-1 and 64Cu-BaBaSar-1 showed improved specificity for the αvβ6 positive tumor in vivo over 64Cu-DOTA-1 and 64Cu-NOTA-1 (+/? tumor uptake ratios—3.82?+/-?0.44, 3.82?±?0.41, 2.58?±?0.58, and 1.29?±?0.14, respectively). Of the four radiotracers, 64Cu-NOTA-1 exhibited the highest liver uptake (10.83?±?0.1 % ID/g at 4 h).Conclusions
We have successfully conjugated, radiolabeled, and assessed the four chelates CB-TE1A1P, DOTA, NOTA, and BaBaSar both in vitro and in vivo. However, the data suggests no clear “best candidate” for the 64Cu-radiolabeling of A20FMDV2, but instead a trade-off between the different properties (e.g., stability, selectivity, pharmacokinetics, etc.) with no obvious effects of the individual chelators. 相似文献8.
Nicolas Nicastro Valentina Garibotto Antoine Poncet Simon Badoud Pierre R. Burkhard 《Molecular imaging and biology》2016,18(2):302-312
Purpose
To overcome the issue of reference values for DaTSCAN® requiring healthy controls, we propose an original approach using scans from individuals with non-degenerative conditions performed at one single center following the same acquisition protocol.Procedures
From a cohort of 970 consecutive patients, we identified 182 patients with a clinical diagnosis of non-degenerative parkinsonism or tremor and a visually normal DATSCAN®. Caudate nucleus (C), putamen (P), and striatum (S) uptake values, C/P ratios, and asymmetry indexes (AI) were calculated using semi-quantitative methods. Outcomes were assessed according to age and gender, and reference limits were established using the percentile approach.Results
A significant negative linear effect of age was found upon striatal nuclei uptake of 0.21–0.22 per decade (6.8 %/decade for striatum), whereas a potential gender influence proved unclear. Inferior reference limits were established at the 5th percentile. C/P ratios and AIs were not influenced by age or gender, and superior reference limits were set at the 95th percentile.Conclusions
We here propose a convenient approach to calculate site-specific reference limits for DaTSCAN® outcomes not requiring scanning healthy controls. The method appears to yield robust values that range within nearly identical limits as those obtained in healthy subjects.9.
Hiroto Kuwabara Yongjun Gao Michael Stabin Jennifer Coughlin Sridhar Nimmagadda Robert F. Dannals Martin G. Pomper Andrew G. Horti 《Molecular imaging and biology》2017,19(2):280-288
Purpose
Currently available positron-emitting radiotracers for imaging of the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) exhibit high and moderate specific binding in the thalamus and extra-thalamic brain regions, respectively. In many neuropsychiatric disorders, α4β2-nAChRs are altered in the extra-thalamic brain regions, but not necessarily in the thalamus. The purpose of this study was to evaluate [18F]XTRA, a new α4β2-nAChR positron emission tomography (PET) radioligand with improved specific binding in extra-thalamic brain regions, in non-human primates.Procedures
The regional distribution of [18F]XTRA in the brain of Papio anubis baboons was evaluated in baseline and blocking experiments. Various PET modeling procedures were used for determination of volume of distribution (V T), binding potential (BPND), and receptor occupancy. Radiation dosimetry for [18F]XTRA was studied in male CD-1 mice and extrapolated to human dosimetry estimates using OLINDA/EXM software.Results
[18F]XTRA was synthesized using an automated radiochemistry module with 25 % decay-corrected radiochemical yield. [18F]XTRA readily enters the baboon brain and specifically labels α4β2-nAChRs. Mathematical modeling demonstrates high binding potential values (BPND = 7 and 1.3 in the thalamus and frontal cortex, respectively). A PET scanning time of 90–120 min was sufficient to obtain stable V T values in the extra-thalamic regions. The extrapolated human effective dose was 0.041 mSv/MBq (0.15 Rem/mCi).Conclusion
[18F]XTRA exhibits improved specific binding in the baboon brain including extra-thalamic regions and it is considered radiologically acceptable for human studies. Further evaluations of [18F]XTRA in human subjects are under way.10.
Mohammad Namavari Ya-Fang Chang Brenda Kusler Shahriar Yaghoubi Beverly S. Mitchell Sanjiv Sam Gambhir 《Molecular imaging and biology》2011,13(5):812-818
Purpose
9-(β-D-Arabinofuranosyl)guanine (AraG) is a guanosine analog that has a proven efficacy in the treatment of T-cell lymphoblastic disease. To test the possibility of using a radiofluorinated AraG as an imaging agent, we have synthesized 2′-deoxy-2′-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG) and investigated its uptake in T cells. 相似文献11.
M. Oberhoffer S. Rußwurm D. Bredle K. Chatzinicolaou K. Reinhart 《Intensive care medicine》2000,26(2):S170-S174
Objectives To determine the correlations and predictive strength of surrogate markers (body temperature, leukocyte count, C-reactive
protein (CRP) and procalcitonin (PCT)) with elevated levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in
septic patients on randomly chosen days.
Design Prospective consecutive case series.
Setting Surgical intensive care unit (ICU) of a university hospital.Patients: Two hundred forty-three patients experiencing ICU stays of longer than 48 h categorized for sepsis according to ACCP/SCCM
Consensus Conference criteria.
Measurements and main results CRP and PCT were both significantly correlated with TNF-α and IL-6. Based on the area under the curve (AUC) of the receiver
operating characteristic (ROC) curves, predictive capability was highest for PCT (0.846 for TNF-α>40 pg/ml and 0.837 for IL-6>500
pg/ml), moderate with CRP (0.744 and 0.748, respectively), and lowest for leukocyte count (0.562 and 0.534, respectively)
and body temperature (0.570 and 0.623, respectively). Sensitivity, specificity, positive and negative predictive values and
test effectiveness all followed this same pattern of being highest for PCT followed by CRP, with leukocyte count and body
temperature being lowest.
Conclusion PCT may be an early and better marker of elevated cytokines than the more classic criteria of inflammation. 相似文献