Somatostatin Receptor Targeting Peptides Research Articles

Increased 68Ga-DOTATATE Uptake in Supraclavicular Brown Adipose Tissue.

Characterization of brown adipose tissue (BAT) 18F-FDG uptake has been well reported; however, 68Ga-DOTA-conjugated somatostatin receptor targeting peptides uptake in BAT is rarely documented. Herein, we report an interesting case of increased 68Ga-DOTATATE uptake in supraclavicular BAT in a young boy with paroxysmal hypertension. The low body mass index and increased perfusion of BAT in response to cold may be significant influencing factors.

Functional Imaging and Peptide Receptor Radionuclide Therapy for Pancreatic Neuroendocrine Tumor

Somatostatin receptors (SSTR) are overexpressed in various tumors including neuroendocrine tumors. In-111 Octreoscan or Ga-68 DOTATOC positron emission tomography/computed tomography (PET/CT) showed these SSTR expressing tumors in whole body of patients. Ga-68 DOTATOC PET/CT has a better sensitivity and resolution than In-111 Octreoscan with single photon emission computed tomography (SPECT)/CT.. The indications of Ga-68 DOTATOC PET/CT are 1) staging: detect sites of primary and metastasis, 2) re-staging: follow-up of patients with known disease to detect residual, recurrent or progressive disease, 3) prognosis & management decisions: determine SSTR status & select patients with SSTR radionuclide therapy, and 4) monitor the response to therapy. Nuclear medicine treatments for neuroendocrine tumors with radioisotope labeling on the somatostatin receptor targeting peptide (peptide receptor radionuclide therapy, PRRT) were conducted in Europe, Australia, and other countries for over 20 years. Eligible patients to be effective to PRRT using Lu-177 DOTATATE can be pre-screened by confirming the expression of somatostatin receptor on tumors using Octreoscan or Ga-68 DOTATOC PET/CT prior to treatment. This pair of molecular targeted treatment and companion diagnostics, so called molecular theranostics makes PRRT a good example for a precision medicine. A multinational clinical trial with the Lu-177 DOTATATE treatment (Lutathera) showed a significant progression free survival over the control group and Ministry of Food and Drug Safety in Korea approved Lutathera. Some doctors are treating patients who are refractory to Lu-177 using Ac-225, an alpha-emitter therapy in Germany and India. The high therapeutic effect of the alpha emitting radionuclides will lead the future of nuclear medicine therapy.

Guideline for PET/CT Imaging of Neuroendocrine Neoplasms with 68Ga-DOTA-conjugated Somatostatin Receptor Targeting Peptides

Guideline for PET/CT Imaging of Neuroendocrine Neoplasms with 68Ga-DOTA-conjugated Somatostatin Receptor Targeting Peptides

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide 47Sc

BackgroundIn molecular imaging and nuclear medicine, theranostic agents that integrate radionuclide pairs are successfully being used for individualized care, which has led to rapidly growing interest in their continued development. These compounds, which are radiolabeled with one radionuclide for imaging and a chemically identical or similar radionuclide for therapy, may improve patient-specific treatment and outcomes by matching the properties of different radionuclides with a targeting vector for a particular tumor type. One proposed theranostic radionuclide is scandium-47 (47Sc, T1/2 = 3.35 days), which can be used for targeted radiotherapy and may be paired with the positron emitting radionuclides, 43Sc (T1/2 = 3.89 h) and 44Sc (T1/2 = 3.97 h) for imaging. The aim of this study was to investigate the photonuclear production of 47Sc via the 48Ti(γ,p)47Sc reaction using an electron linear accelerator (eLINAC), separation and purification of 47Sc, the radiolabeling of somatostatin receptor-targeting peptide DOTATOC with 47Sc, and in vitro receptor-mediated binding of [47Sc]Sc-DOTATOC in AR42J somatostatin receptor subtype two (SSTR2) expressing rat pancreatic tumor cells.ResultsThe rate of 47Sc production in a stack of natural titanium foils (n = 39) was 8 × 107 Bq/mA·h (n = 3). Irradiated target foils were dissolved in 2.0 M H2SO4 under reflux. After dissolution, trivalent 47Sc ions were separated from natural Ti using AG MP-50 cation exchange resin. The recovered 47Sc was then purified using CHELEX 100 ion exchange resin. The average decay-corrected two-step 47Sc recovery (n = 9) was (77 ± 7)%. A radiolabeling yield of > 99.9% of [47Sc]Sc-DOTATOC (0.384 mg in 0.3 mL) was achieved using 1.7 MBq of 47Sc. Blocking studies using Octreotide illustrated receptor-mediated uptake of [47Sc]Sc-DOTATOC in AR42J cells.Conclusions47Sc can be produced via the 48Ti(γ,p)47Sc reaction and separated from natural Ti targets with a yield and radiochemical purity suitable for radiolabeling of peptides for in vitro studies. The data in this work supports the potential use of eLINACs for studies of photonuclear production of medical radionuclides and the future development of high-intensity eLINAC facilities capable of producing relevant quantities of carrier-free radionuclides currently inaccessible via routine production pathways or limited due to costly enriched targets.

Performance of 68Ga-DOTA–Conjugated Somatostatin Receptor–Targeting Peptide PET in Detection of Pheochromocytoma and Paraganglioma: A Systematic Review and Metaanalysis

We performed a systematic review and metaanalysis of the performance of 68Ga-DOTA-conjugated somatostatin receptor-targeting peptide (68Ga-DOTA-SST) PET in the detection of pheochromocytomas and paragangliomas (PPGLs). Methods: PubMed and Embase were searched until May 8, 2018. We included studies that reported the detection rate of 68Ga-DOTA-SST PET in patients with PPGLs. Detection rates were pooled using a random-effects model. Subgroup analyses and metaregression were performed to explore the cause of heterogeneity. Results: Thirteen studies were included for qualitative synthesis. Per-lesion detection rates of 68Ga-DOTA-SST PET were consistently higher (ranging from 92% to 100%) than other imaging modalities, including 18F-fluorohydroxyphenylalanine (18F-FDOPA) PET, 18F-FDG PET, and 123/131I-metaiodobenzylguanidine (123/131I-MIBG) scintigraphy. However, in patients with polycythemia/paraganglioma syndrome, the detection rate of 68Ga-DOTA-DOTATATE PET was 35%. Nine studies (215 patients) with no specific inclusion criteria for subtype were quantitatively synthesized. The pooled detection rate was 93% (95% confidence interval [CI], 91%-95%), which was significantly higher than that of 18F-FDOPA PET (80% [95% CI, 69%-88%]), 18F-FDG PET (74% [95% CI, 46%-91%]), and 123/131I-MIBG scan (38% [95% CI, 20%-59%], P < 0.001 for all). A greater prevalence of head and neck paragangliomas was associated with higher detection rates of 68Ga-DOTA-SST PET (P = 0.0002). Conclusion: 68Ga-DOTA-SST PET exhibited superior performance for lesion detection, over other functional imaging modalities, in patients with PPGLs, with the exception of polycythemia/paraganglioma syndrome. This might suggest 68Ga-DOTA-SST PET as a first-line imaging modality for the primary staging of PPGL or the restaging of PPGL with unknown genetic status.

Theranostic radiopharmaceuticals: established agents in current use

Although use of the term "theranostic" is relatively recent, the concept goes back to the earliest days of nuclear medicine, with the use of radioiodine for diagnosis and therapy of benign and malignant thyroid disease being arguably the most successful molecular radiotherapy in history. A diagnostic scan with 123I-, 124I-, or a low activity of 131I-iodide is followed by therapy with high activity 131I-iodide. Similarly, adrenergic tumours such as phaeochromocytoma and neuroblastoma can be imaged with 123I-metaiodobenzylguanidine and treated with 131I-metaiodobenzylguanidine. Bone scintigraphy can be used to select patients with painful bone metastases from prostate cancer who may benefit from treatment with beta- or alpha-particle emitting bone seeking agents, the most recent and successful of which is 223Ra radium chloride. Anti-CD20 monoclonal antibodies can be used to image and treat non-Hodgkins lymphoma, though this has not been as commercially successful as initially predicted. More recently established theranostics include somatostatin receptor targeting peptides for diagnosis and treatment of neuroendocrine tumours with agents such as 68Ga-DOTATATE and 177Lu-DOTATATE, respectively. Finally, agents which target prostate-specific membrane antigen are becoming increasingly widely available, despite the current lack of a commercial product. With the recent licensing of the somatostatin peptides and the rapid adoption of 68Ga- and 177Lu-labelled prostate-specific membrane antigen targeting agents, we have built upon the experience of radioiodine and are already seeing a great expansion in the availability of widely accepted theranostic radiopharmaceuticals.

Erratum to: Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA.

Erratum to : Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA.

Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA.

Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using 68Ga-DOTA-conjugated peptides, as well as 18F-DOPA imaging for various neuroendocrine neoplasms. The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with 68Ga-conjugated peptides has been revised and updated with the relevant and recent literature in the field with contribution of distinguished experts.

Update:Improvement Strategies for Peptide Receptor Scintigraphy and Radionuclide Therapy

Somatostatin receptor-targeting peptides are widely used for the imaging and therapy of neuroendocrine tumors. Peptide-receptor radionuclide therapy (PRRT) in neuroendocrine tumor patients with radiolabeled somatostatin analogs has resulted in symptomatic improvement, prolonged survival, and enhanced quality of life. The side-effects of PRRT are few and mostly mild, certainly when using kidney protective agents. If a more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasized or inoperable neuroendocrine gastroenteropancreatic tumors. Yet, much profit can be gained from improving the receptor-targeting strategies available and developing new strategies. This review presents an overview of several options to optimize receptor-targeted imaging and radionuclide therapy. These include the optimization of peptide analogs, increasing the number of receptors on the tumor site, and combining PRRT with other treatment strategies. The development of new peptide analogs with increased receptor-binding affinity and improved stability might lead to a higher accumulation of radioactivity inside tumor cells. Analogs of somatostatin have been widely studied. However, much profit can be gained in improving peptide analogs targeting other tumor-related receptors, including gastrin-releasing peptide (GRP) receptors, neurotensin (NT) receptors, cholecystokinin (CCK) receptors, and glucagon-like peptide-1 (GLP-1) receptors. Several peptide analogs targeting these receptors are well on their way to clinical utilization. The literature shows that it is possible to increase the receptor density on tumor cells by using different methods, which results in higher binding and internalization rates and thus a higher contrast during peptide-receptor scintigraphy. In PRRT treatment, this would enable the administration of higher therapeutic doses to tumors, which might lead to a higher cure rate in patients. Combinations of radionuclide therapy with other treatment modalities, such as chemotherapy or pretreatment with radiosensitizers, might increase the impact of the treatment. Further, the administration of higher dosages of radioactivity to the patient, enabled by combinations of PRRT with strategies reducing the radiation dose to healthy organs, will improve the outcome of tumor treatment. Also, targeting one or several tumor-specific receptors by using combinations of therapeutic agents, as well as by reducing nontarget uptake of radioactivity, will enlarge the therapeutic window of PRRT. Clinical studies will provide more insight in the effects of combining treatment strategies in cancer patients.

Radiolabeled RGD-DTPA-Tyr3-octreotate for receptor-targeted radionuclide therapy.

The aim of this study was to develop and investigate a radiopeptide for the treatment of cancers which overexpress cell surface somatostatin receptors. The new radiopharmaceutical is composed of a somatostatin receptor-targeting peptide, a chelator (DTPA) to enable radiolabeling, and an apoptosis-inducing RGD (arginine-glycine-aspartate) peptide moiety. The receptor-targeting peptide portion of the molecule, Tyr3-octreotate, is specific for the somatostatin subtype-2 cell surface receptor (sst2), which is overexpressed on many tumor cells. Because of the rapid endocytosis of the somatostatin receptor, the entire molecule can thus be internalized, allowing the RGD portion to activate intracellular caspases, which in turn promotes apoptosis. In this paper, we present the synthesis and the in vitro and in vivo tumor binding and internalization characteristics of this hybrid peptide. In vitro internalization into sst2-positive tumor cells of the radiolabeled hybrid peptide appeared to be a rapid process and could be blocked by an excess of unlabeled octreotide, indicating an sst2-specific process. Tumor uptake in vivo in rats of radiolabeled RGD-DTPA-Tyr3-octreotate was in agreein vitro data and similar to that of radiolabeled DOTA-Tyr3-octreotate. The combined molecule is expected to significantly enhance the therapeutic efficacy of the somatostatin-based agent.