Zhanhong Wu

In vivo imaging of transplanted islets with 64Cu-DO3A-VS-Cys40-Exendin-4 by targeting GLP-1 receptor.

Glucagon-like peptide 1 receptor (GLP-1R) is highly expressed in pancreatic islets, especially on β-cells. Therefore, a properly labeled ligand that binds to GLP-1R could be used for in vivo pancreatic islet imaging. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), a more stable agonist of GLP-1 such as Exendin-4 is a preferred imaging agent. In this study, DO3A-VS-Cys(40)-Exendin-4 was prepared through the conjugation of DO3A-VS with Cys(40)-Exendin-4. The in vitro binding affinity of DO3A-VS-Cys(40)-Exendin-4 was evaluated in INS-1 cells, which overexpress GLP-1R. After (64)Cu labeling, biodistribution studies and microPET imaging of (64)Cu-DO3A-VS-Cys(40)-Exendin-4 were performed on both subcutaneous INS-1 tumors and islet transplantation models. The subcutaneous INS-1 tumor was clearly visualized with microPET imaging after the injection of (64)Cu-DO3A-VS-Cys(40)-Exendin-4. GLP-1R positive organs, such as pancreas and lung, showed high uptake. Tumor uptake was saturable, reduced dramatically by a 20-fold excess of unlabeled Exendin-4. In the intraportal islet transplantation models, (64)Cu-DO3A-VS-Cys(40)-Exendin-4 demonstrated almost two times higher uptake compared with normal mice. (64)Cu-DO3A-VS-Cys(40)-Exendin-4 demonstrated persistent and specific uptake in the mouse pancreas, the subcutaneous insulinoma mouse model, and the intraportal human islet transplantation mouse model. This novel PET probe may be suitable for in vivo pancreatic islets imaging in the human.

64Cu labeled sarcophagine exendin-4 for microPET imaging of glucagon like peptide-1 receptor expression

The Glucagon-like peptide 1 receptor (GLP-1R) has become an important target for imaging due to its elevated expression profile in pancreatic islets, insulinoma, and the cardiovascular system. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), several studies have conjugated different chelators to a more stable analog of GLP-1 (such as exendin-4) as PET or SPECT imaging agents with various advantages and disadvantages. Based on the recently developed Sarcophagin chelator, here, we describe the construction of GLP-1R targeted PET probes containing monomeric and dimeric exendin-4 subunit. The in vitro binding affinity of BarMalSar-exendin-4 and Mal2Sar-(exendin-4)2 was evaluated in INS-1 cells, which over-express GLP-1R. Mal2Sar-(exendin-4)2 demonstrated around 3 times higher binding affinity compared with BaMalSar-exendin-4. After 64Cu labeling, microPET imaging of 64Cu-BaMalSar-exendin-4 and 64Cu-Mal2Sar-(exendin-4)2 were performed on subcutaneous INS-1 tumors, which were clearly visualized with both probes. The tumor uptake of 64Cu-Mal2Sar-(exendin-4)2 was significantly higher than that of 64Cu-BaMaSarl-exendin-4, which could be caused by polyvalency effect. The receptor specificity of these probes was confirmed by effective blocking of the uptake in both tumor and normal positive organs with 20-fold excess of unlabeled exendin-4. In conclusion, sarcophagine cage conjugated exendin-4 demonstrated persistent and specific uptake in INS-1 insulinoma model. Dimerization of exendin-4 could successfully lead to increased tumor uptake in vivo. Both 64Cu-BaMalSar-exendin-4 and 64Cu-Mal2Sar-(exendin-4)2 hold a great potential for GLP-1R targeted imaging.

18F-labeled proteins.

Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. In particular, the interest in (18)F-labeled proteins remains high for both diagnoses and therapy monitoring purposes. The development of labeling strategies for the synthesis of new (18)F labeled protein is, however, not trivial. (18)F-containing prosthetic groups are often required for protein labeling to obtain high yield under mild labeling conditions and keep the bioactive character of the proteins. This Review highlights key aspects of protein (18)F-labeling method and discussed representative examples including (18)F-labeled human serum albumin, (18)F-labeled Annexin V, (18)F-labeled HER2 affibody, and (18)F-labeled low density lipoprotein.

Pre-clinical evaluation of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 for imaging of insulinoma

INTRODUCTION Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma. METHODS [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficient mice at two different doses of peptide: 2.5μg/kg (baseline) and 100μg/kg (block). In vivo imaging of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). RESULTS GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 showed significant uptake (p≤0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [(11)C]5-HTP. CONCLUSION [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo.

Evaluation of 18F-DEG-VS-NT for NTR1 targeted imaging in prostate cancer

This interesting book is one of a series that aims to provide a systematic framework for understanding imaging choices based on evidence reported in the literature. Written mostly by radiologists and clinicians, the book is intended to be a reference for decision making in clinical practice and contains information on the use of neuroimaging in every possible clinical case of brain, spine, and head and neck disorders. The imaging modalities that are discussed include CT, MR imaging, MR angiography, SPECT (mostly of the spine), and PET (mostly of head and neck masses). On the basis of the clinical literature as evaluated from cost-effectiveness-analysis and evidence-based-medicine perspectives, each chapter poses questions such as “in this condition, which imaging method is warranted, and why?” and then answers those questions. The authors pay most attention to the results of clinical trials that did or did not include neuroimaging options, attempting to prove or disprove the value of neuroimaging studies in the outcomes of patients with cerebrovascular diseases, spine disorders, or head and neck cancers. The authors also predict the future value of newer neuroimaging methods that may soon be used to evaluate some of the more incomprehensible and intractable pediatric neurodevelopmental and neurodegenerative diseases. Interestingly, every chapter has a section that describes further research needed to optimize the use of current neuroimaging methods or, in the case of MR imaging, to expand its use to newer sequences. Almost all the chapters include physiologic imaging as an example of such a modality, along with the use of SPECT and PET for seizure disorders; bone SPECT for spinal injection for low back pain; PET for brain cancer, neck masses, neck adenopathy, and diagnosis of cervical lymph node metastasis in head and neck cancer; and MR spectroscopy. Readers can easily refer to this book for the answers to probable clinical questions and supporting evidence for those answers. Readers can also use the “Key Points” sections to quickly determine whether a certain modality, such as PET or SPECT, is dealt with in those questions. The chapters are in a hierarchical format that allows readers to quickly find specific questions and answers of interest and then broaden their search if desired. The consistency in the depth and style of each chapter will assure readers that each is consistently informative and credible. For nuclear medicine physicians, the information on CT, MR imaging, and angiography for brain, spine, and head and neck disorders will help them grasp the big picture on the current best practice and changes expected in the near future. The only area that is lacking is information about nuclear medicine imaging—a surprising shortcoming considering the comprehensiveness of the book, and I frowned to see that many chapters described 18F-FDG PET using just the generic term PET. This lack may have occurred because the literature does not include enough publications with sound evidence supporting the use of nuclear medicine imaging in clinical decision making, which would be required in a book on evidence-based medicine such as this one. Another possibility is that the authors simply chose not to describe evidence in the field of nuclear medicine. For example, in the chapter on seizure disorders, 18F-FDG PET is cited with less frequency than in the literature, and in the chapters on acute ischemic stroke and atherosclerotic disease of the cervical carotid artery, I would have expected acetazolamide stress SPECT (either 123I-b-methyliodophenylpentadecanoic acid or 99mTchexamethylpropyleneamine oxime) to be described but it was entirely left out. Likewise, the chapter on brain cancer neglected to mention 11C-methionine PET. Omitting evidence-based information on various uses of SPECT and PET warrants the issuing of a new edition that is truly about neuroimaging instead of merely radiologic neuroimaging. This book would be best utilized by clinicians who are interested in fields other than their own, such as a neurovascular expert who is interested in epilepsy or neurodevelopmental disorders (attention deficit–hyperactivity disorder or autism spectrum disorder) or a nuclear medicine physician who is interested in neuroimaging of patients undergoing endovascular treatment for acute ischemic stroke or patients undergoing spinal injections for low back pain. If readers are interested in an in-depth, balanced interpretation of their own field, they may find other, more specialized references and books preferable to this one. However, this book is the right one for readers interested in how to collect and combine a database to understand the currently optimal, recognized clinical use of a neuroimaging modality and for readers interested in the scientific background for the state-of-the-art use of CT, MR imaging, and angiography. The beauty of this book is that parts I and II describe the principles of evidence-based imaging and neuroimaging in the radiologic field and compose an ideal introduction to the remainder of the book. Part II imparts knowledge about the decision-support process, as well as covering how best to use neuroimaging as a screening tool and how to handle any incidental findings. Also detailed is how to comply with the economic and regulatory changes in the United States—information that readers in Asia and Europe can apply by analogy to their own regulatory situation. I believe that the timing of this book is perfect from the perspective of health care reform in the United States, because neuroimaging is as yet neither an integrative diagnostic procedure (unlike auscultation or palpation) nor an independent procedure. Neuroimaging is costly in both money and time, and its use in clinical practice requires sufficient supporting evidence to persuade layperson policy makers and referring physicians. If we, the nuclear medicine physicians, want our nuclear neuroimaging to be used more often by clinicians and approved by the health-care system, we now know what data we should collect and publish so that secondary literature such as the Cochrane Library or this type of book will reflect our consensus. Reading this book cover to cover was an enlightening adventure for me, educational yet sometimes confusing or frustrating. Certain terms are abbreviated differently COPYRIGHT