Receptors for the incretin glucagon-like peptide-1 (GLP-1R) have been found overexpressed in selected types of human tumors and may, therefore, play an increasingly important role in endocrine ...gastrointestinal tumor management. In particular, virtually all benign insulinomas express GLP-1R in high density. Targeting GLP-1R with indium-111, technetium-99m or gallium-68-labeled exendin-4 offers a new approach that permits the successful localization of small benign insulinomas. It is likely that this new non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. In contrast to benign insulinomas, malignant insulin-secreting neuroendocrine tumors express GLP-1R in only one-third of the cases, while they more often express the somatostatin subtype 2 receptors. Importantly, one of the two receptors appears to be always overexpressed. In special cases of endogenous hyperinsulinemic hypoglycemia (EHH), that is, in the context of MEN-1 or adult nesidioblastosis GLP-1R imaging is useful whereas in postprandial hypoglycemia in the context of bariatric surgery, GLP-1R imaging is probably not helpful. This review focuses on the potential use of GLP-1R imaging in the differential diagnosis of EHH.
Receptor targeting with radiolabelled peptides has become very important in nuclear medicine and oncology in the past few years. The overexpression of many peptide receptors in numerous cancers, ...compared to their relatively low density in physiological organs, represents the molecular basis for in vivo imaging and targeted radionuclide therapy with radiolabelled peptide-based probes. The prototypes are analogs of somatostatin which are routinely used in the clinic. More recent developments include somatostatin analogs with a broader receptor subtype profile or with antagonistic properties. Many other peptide families such as bombesin, cholecystokinin/gastrin, glucagon-like peptide-1 (GLP-1)/exendin, arginine-glycine-aspartic acid (RGD) etc. have been explored during the last few years and quite a number of potential radiolabelled probes have been derived from them. On the other hand, a variety of strategies and optimized protocols for efficient labelling of peptides with clinically relevant radionuclides such as
99m
Tc, M
3+
radiometals (
111
In,
86/90
Y,
177
Lu,
67/68
Ga),
64/67
Cu,
18
F or radioisotopes of iodine have been developed. The labelling approaches include direct labelling, the use of bifunctional chelators or prosthetic groups. The choice of the labelling approach is driven by the nature and the chemical properties of the radionuclide. Additionally, chemical strategies, including modification of the amino acid sequence and introduction of linkers/spacers with different characteristics, have been explored for the improvement of the overall performance of the radiopeptides, e.g. metabolic stability and pharmacokinetics. Herein, we discuss the development of peptides as radiopharmaceuticals starting from the choice of the labelling method and the conditions to the design and optimization of the peptide probe, as well as some recent developments, focusing on a selected list of peptide families, including somatostatin, bombesin, cholecystokinin/gastrin, GLP-1/exendin and RGD.
Radiolabeled somatostatin receptor (sstr) antagonists have shown superiority in different preclinical and clinical settings compared with the well-established and clinically used agonists for ...targeting sstr-expressing tumors, with regard to pharmacokinetics, tumor uptake, and retention. The theranostic pair
Lu-OPS201/
Ga-OPS202, based on the sstr2 antagonist JR11 (Cpa-cd-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys-d-Tyr-NH
), is the most advanced pair of the antagonist family in terms of preclinical development and is currently under clinical evaluation. OPS201 and OPS202 share the same amino acid sequence (JR11) but feature different conjugated chelators needed for radiolabeling, DOTA for OPS201 and NODAGA for OPS202. In this review, the design and development of the peptidic analog, JR11, and the selection of chelators and radiometals that led to
Lu-OPS201/
Ga-OPS202 are discussed. Furthermore, the preclinical evaluation of both radiolabeled analogs from bench to bedside and the clinical trials involving the theranostic pair are presented.
Peptide Receptor Radionuclide Therapy (PRRT) is an established treatment for non-operable or metastatic neuroendocrine neoplasms that express highly and frequently somatostatin receptors. More ...generally, PRRT is an attractive therapy option for delivering cytotoxic radiation to tumor cells through specific binding of a radiolabeled peptide to a molecular target. The development of imaging companions gave rise to the concept of radiotheranostics, important for in vivo tumor detection, characterization, staging but also, and more importantly, for individual patient selection and treatment. The success of somatostatin receptor targeting paved the way for the clinical translation of other peptide-based radiopharmaceuticals targeting, e.g. the receptors Cholecystokinin 2, Gastrin Releasing Peptide (GRPR), Neurokinin-1 and C-X-C motif chemokine 4 (CXCR4). While historically the Auger emitter
In and the high-energy β- emitter
Y were used, the vast majority of PRRT are currently performed with the medium-energy β- emitter
Lu, while α emitters are increasingly studied in various clinical applications.
During the past decade radiolabeled RGD-peptides have been extensively studied to develop site-directed targeting vectors for integrins. Integrins are heterodimeric cell-surface adhesion receptors, ...which are upregulated in cancer cells and neovasculature during tumor angiogenesis and recognize the RGD aminoacid sequence. In the present study, we report the synthesis and development of two derivatives of the Nε-Lys derivatized cyclic Arg-Gly-Asp-d-Phe-Lys peptide, namely of cRGDfKHis and cRGDfK-CPA (CPA: 3-l-Cysteine Propionic Acid), radiolabeled via the 99mTc(H2O)3(CO)3+ metal aquaion at a high yield even at low concentrations of 10–5M (>87%) for cRGDfK-10–5M (>93%) for cRGDfK-CPA. Radiolabeled peptides were characterized with regard to their stability in saline, in His/Cys solutions, as well as in plasma, serum and tissue homogenates and were found to be practically stable. Internalization and efflux assays using αvβ3-receptor-positive MDA-MB 435 breast cancer cells showed a good percentage of quick internalization (29.1±9.8% for 99mTc-HiscRGDfK and 37.0±0.7% for 99mTc-CPA-cRGDfK at 15min) and no retention of radioactivity for both derivatives. Their in vivo behavior was assessed in normal mice and pathological SCID mice bearing MDA-MB 435 ανβ3 positive breast tumors. Both presented fast blood clearance and elimination via both the urinary and hepatobiliary systems, with 99mTc-His-cRGDfK remaining for a longer time than 99mTc-CPA-cRGDfK in all organs examined. Tumor uptake 30min pi was higher for 99mTc-CPAcRGDfK (4.2±1.5% ID/g) than for 99mTc-His-cRGDfK (2.8±1.5% ID/g). Dynamic scintigraphic studies showed that the tumor could be visualized better between 15 and 45min pi for both radiolabeled compounds but low delineation occurred due to high abdominal background. It was finally noticed that the accumulated activity on the tumor site was depended on the size of the experimental tumor; the smaller the size, the higher was the radioactivity concentration.
Radiopeptide imaging and therapy in Europe Ambrosini, Valentina; Fani, Melpomeni; Fanti, Stefano ...
Journal of Nuclear Medicine,
12/2011, Letnik:
52 Suppl 2, Številka:
Supplement 2
Journal Article
Recenzirano
Odprti dostop
Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in ...nuclear medicine departments in Europe. The target receptors belong to the large family of G-protein-coupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide (111)In-pentetreotide, efficient SPECT tracers labeled with (99m)Tc and PET agents based on generator-produced (68)Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the β(-) emitters (90)Y and (177)Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. (111)In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre- and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin- and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. (99m)Tc-labeled peptides for SPECT and (68)Ga-, as well as (64)Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a (177)Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; the natural ligand is substance P, which was metabolically stabilized, labeled with (90)Y and (213)Bi, and injected into resection cavities or directly into tumors, which were critically located via a catheter system. The major advantage of this approach appeared to be the facilitated resectability of tumors, particularly in those patients who had been treated up front with the locoregional approach. It appears that neoadjuvant treatment before resection is a valid concept. Finally, another peptide family, the arginine-glycine-aspartate-based radiotracers, has made it to the clinic labeled with a variety of radioisotopes for monitoring the integrins α(v)β(3) overexpressed during tumor angiogenesis.
The glucagon-like peptide-1 receptor (GLP-1R) is an emerging target due to its high expression in benign insulinomas as well as in islet cell hypertrophia/hyperplasia (nesidioblastosis) and ...pancreatic β-cells. In 2008, occult insulinomas were localized for the first time in men using the metabolically stable radiolabeled glucagon-like peptide-1 (GLP-1) agonist Lys
(Ahx-DTPA-
In)NH
-exendin-4 (
In-DTPA-exendin-4). Afterward, several radiopharmaceuticals for GLP-1R PET/CT imaging were synthesized and evaluated, for example, Nle
,Lys
(Ahx-DOTA-
Ga)NH
-exendin-4 (
Ga-DOTA-exendin-4), Cys
(MAL-NOTA-
Ga)NH
-exendin-4 (
Ga-NOTA-exendin-4), and Lys
(NODAGA-
Ga)NH
-exendin-4 (
Ga-NODAGA-exendin-4). Several prospective comparison studies provided evidence that GLP-1R PET/CT is significantly more sensitive than contrast-enhanced MRI (ceMRI), contrast-enhanced CT (ceCT), GLP-1R SPECT/CT, somatostatin receptor PET/CT, and SPECT/CT in the detection of benign insulinomas, and insulinomas in the context of multiple endocrine neoplasia type 1. As a result, the European Neuroendocrine Tumor Society guidelines recommend GLP-1R imaging or selective intraarterial calcium stimulation and venous sampling (ASVS) in patients for whom there is a clinical suspicion of having an insulinoma but who have a negative ceMRI/ceCT or negative endoscopic ultrasound. Furthermore, there is growing evidence that GLP-1R PET/CT can visualize and localize adult nesidioblastosis. This is clinically relevant as the distinction between focal and diffuse nesidioblastosis is critical in directing a therapeutic strategy in these patients. Prospective studies have proven the clinical relevance of GLP-1R imaging as it is often the only imaging modality able to localize the insulinoma or nesidioblastosis. It is therefore likely that this noninvasive imaging modality will replace the invasive localization of insulinomas using ASVS. More experimental indications for GLP-1R imaging include the diagnosis of an insulinoma/nesidioblastosis in patients with postprandial hypoglycemia after bariatric bypass surgery and monitoring β-cells in patients with brittle type 1 diabetes after islet-cell transplantation. We believe that these indications and possibly future indications will bring GLP-1R imaging to the clinic.
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