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Positron Emission Tomography (PET) has become a popular imaging technique widely used for diagnostic purposes. To date, much attention has been devoted to (18)F-fluoride because of the characteristics of its nuclear decay, as well as its relative ease of preparation from (18)O-water. However, with a half-life of 110 minutes, swift and efficient incorporation of (18)F-fluorine into biomolecules is necessary to minimize loss of activity. Therefore, the discovery of rapid and reliable incorporation of (18)F-fluorine atoms into biomolecules would be highly beneficial, especially if these protocols can be carried out directly in irradiated 18O-water. In the study published in the American Journal of Nuclear Medicine and Molecular Imaging, cyclo-RGD-(18)F-aryltrifluoroborate conjugates were prepared based on one-step and one-pot-two-step methods. This paper represents recent efforts on the design and development of novel PET tracers based on the "Kit like" (18)F labeling method.

A rapid, efficient, and catalyst-free click chemistry method for the construction of (64)Cu-labeled PET imaging probes was reported based on the strain-promoted aza-dibenzocyclooctyne ligation. This new method was exemplified in the synthesis of (64)Cu-labeled RGD peptide for PET imaging of tumor integrin αvβ3 expression in vivo. The catalyst-free click chemistry reaction proceeded with a fast rate and eliminated the contamination problem of the catalyst Cu(I) ions interfering with the (64)Cu radiolabeling procedure under the conventional Cu-catalyzed 1,3-dipolar cycloaddition condition. The new strategy is simple and robust, and the resultant (64)Cu-labeled RGD probe was obtained in an excellent yield and high specific activity. PET imaging and biodistribution studies revealed significant, specific uptake of the "click" (64)Cu-labeled RGD probe in integrin αvβ3-positive U87MG xenografts with little uptake in nontarget tissues. This new approach is versatile, which warrants a wide range of applications for highly diverse radiometalated bioconjugates for radioimaging and radiotherapy.

Purpose: The aim of this study is to determine if dynamic optical imaging could provide comparable kinetic parameters to that of dynamic PET imaging by a near-infrared dye/(64)Cu dual-labeled cyclic RGD peptide., Methods: The integrin α(v)β(3) binding RGD peptide was conjugated with a macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for copper labeling and PET imaging and a near-infrared dye ZW-1 for optical imaging. The in vitro biological activity of RGD-C(DOTA)-ZW-1 was characterized by cell staining and receptor binding assay. Sixty-min dynamic PET and optical imaging were acquired on a MDA-MB-435 tumor model. Singular value decomposition (SVD) method was applied to compute the dynamic optical signal from the two-dimensional optical projection images. Compartment models were used to quantitatively analyze and compare the dynamic optical and PET data., Results: The dual-labeled probe (64)Cu-RGD-C(DOTA)-ZW-1 showed integrin specific binding in vitro and in vivo. The binding potential (Bp) derived from dynamic optical imaging (1.762 ± 0.020) is comparable to that from dynamic PET (1.752 ± 0.026)., Conclusion: The signal un-mixing process using SVD improved the accuracy of kinetic modeling of 2D dynamic optical data. Our results demonstrate that 2D dynamic optical imaging with SVD analysis could achieve comparable quantitative results as dynamic PET imaging in preclinical xenograft models.

Purpose We and others have reported that Sarcophagine-based bifunctional chelators could be effectively used in the syntheses of (64)Cu radiopharmaceuticals. The resulted (64)Cu-Sarcophagine complexes demonstrated great in vivo stability. The goal of this study was to further derivatize Sarcophagine cage with amino and maleimide functional groups for conjugation with bioligands.Methods Starting from DiAmSar, three novel chelators (AnAnSar, BaMalSar, and Mal(2)Sar) with two functional groups have been synthesized. Among those, BaMalSar and Mal(2)Sar have been conjugated with cyclic peptide c(RGDyC) (denoted as RGD) and the resulted conjugates, BaMalSar-RGD and Mal(2)Sar-RGD(2) have been labeled with (64)Cu. The tumor targeting efficacy of (64)Cu-labeled RGD peptides were evaluated in a subcutaneous U87MG glioblastoma xenograft model.Results The conjugates, BaMalSar-RGD and Mal(2)Sar-RGD(2) could be labeled with (64)CuCl(2) in 10 min with high purity (>98%) and high radiochemical yield (>90%). Both (64)Cu-BaMalSar-RGD and (64)Cu-Mal(2)Sar-RGD(2) exhibited high tumor uptake and tumor-to-normal tissue ratios.Conclusion Three novel chelators with two functional groups have been developed based on Sarcophagine cage. The platform developed in this study could have broad applications in the design and synthesis of( 64)Cu-radiopharmaceuticals.

Over the last decade, integrin α(v)β(3) has been studied with every single molecular imaging modality. Since no single modality is perfect and sufficient to obtain all the necessary information for a particular question, combination of certain molecular imaging modalities can offer synergistic advantages over any modality alone. This review will focus on multimodality imaging of integrin α(v)β(3) expression, where the contrast agent used can be detected by two or more imaging modalities, such as combinations of PET and optical, SPECT and fluorescence, PET and MRI, SPECT and MRI, and lastly, MRI and fluorescence. Most of these agents are based on certain type(s) of nanoparticles. Contrast agents that can be detected by more than two imaging modalities are expected to emerge in the future and a PET/MRI/fluorescence agent will likely find the most future biomedical/clinical applications. Big strides have been made over the last decade for imaging integrin α(v)β(3) expression and several PET/SPECT probes have been tested in human studies. For dualmodality and multimodality imaging applications, a number of proof-of-principle studies have been reported which opened up many new avenues for future research. The next decade will likely witness further growth and continued prosperity of molecular imaging studies focusing on integrin α(v)β(3), which can eventually impact patient management.

The integrin family is a group of transmembrane glycoprotein comprised of 19 α- and 8 β-subunits that are expressed in 25 different α/β heterodimeric combinations on the cell surface. Integrins play critical roles in many physiological processes, including cell attachment, proliferation, bone remodeling, and wound healing. Integrins also contribute to pathological events such as thrombosis, atherosclerosis, tumor invasion, angiogenesis and metastasis, infection by pathogenic microorganisms, and immune dysfunction. Among 25 members of the integrin family, the α(v)β(3) is studied most extensively for its role of tumor growth, progression and angiogenesis. In contrast, the α(IIb)β(3 )is expressed exclusively on platelets, facilitates the intercellular bidirectional signaling ("inside-out" and "outside-in") and allows the aggregation of platelets during vascular injury. The α(IIb)β(3) plays an important role in thrombosis by its activation and binding to fibrinogen especially in arterial thrombosis due to the high blood flow rate. In the resting state, the α(IIb)β(3) on platelets does not bind to fibrinogen; on activation, the conformation of platelet is altered and the binding sites of α(IIb)β(3 )are exposed for fibrinogen to crosslink platelets. Over the last two decades, integrins have been proposed as the molecular targets for diagnosis and therapy of cancer, thrombosis and other diseases. Several excellent review articles have appeared recently to cover a broad range of topics related to the integrin-targeted radiotracers and their nuclear medicine applications in tumor imaging by single photon emission computed tomography (SPECT) or a positron-emitting radionuclide for positron emission tomography (PET). This review will focus on recent developments of α(v)β(3)-targeted radiotracers for imaging tumors and the use of α(IIb)β(3)-targeted radiotracers for thrombosis imaging, and discuss different approaches to maximize the targeting capability of cyclic RGD peptides and improve the radiotracer excretion kinetics from non-cancerous organs. Improvement of target uptake and target-to-background ratios is critically important for target-specific radiotracers.

PET imaging of integrin αvβ3 expression has been studied intensely by the academia and recently also by the industry. Imaging of integrin αvβ3 expression is of great potential value, as the integrin αvβ3 is a key player in tumor metastasis and angiogenesis. Therefore PET imaging of this target might be a suitable in-vivo biomarker of angiogenesis and metastatic potential of tumors. In this manuscript, the various strategies for PET imaging of the integrin αvβ3 will be summarized, including monomeric and multimeric radiolabelled RGD peptides and nanoparticles. While most experiments have been performed using preclinical tumor models, more and more clinical results on PET imaging of αvβ3 expression are available and will be discussed in detail. However, while a multitude of radiotracer strategies have been successfully evaluated for PET imaging of αvβ3, the ultimate clinical value of this new imaging biomarker still has to be evaluated in large clinical trials.

Objective: To detect the expression and clinical significances of Lewis y antigen and integrin αv, β3 in epithelial ovarian tumors, and to explore the expression correlation between Lewis y antigen and integrin αv, β3., Methods: Immunohistochemical staining was performed in 95 cases of epithelial ovarian cancer, 37 cases of borderline tumors, 20 cases of benign tumors, and 20 cases of normal ovarian tissue, for the detection of Lewis y antigen and integrin αv, β3 expressions, and to analyze the relationship between Lewis y antigen and integrin, and the relationship between clinical and pathological parameters of ovarian cancer. In addition, immunofluorescence double labeling was utilized to detect the expression correlation between Lewis y antigen and integrin αv, β3 in ovarian cancer., Results: In epithelial ovarian tumors, the expression rate of Lewis y antigen was 81.05%, significantly higher than that of borderline (51.53%) (P < 0.05) and benign (25%) (P < 0.01) tumors, and normal ovarian tissues (0) (P < 0.01). The expression rate of integrin αv, β3 in malignant epithelial ovarian tumors was 78.95% and 82.11%, respectively, significantly higher than that of the borderline (45.94%, 40.54%) (both P < 0.05), benign group (10.00%, 15.00%) (both P < 0.01) and normal ovary group (5%, 15%) (both P < 0.01)., Conclusions: Lewis y and integrins αv, β3 are relevant to pelvic and abdominal diffusion and metastasis of ovarian cancer cells, suggesting that these two molecules mediate a boosting function for tumor metastasis.