Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [In]In-Radioligands: Synthesis and Preclinical Profile.

The overexpression of one or more somatostatin receptors (SSTR) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of "pansomatostatin" analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy of currently applied SSTR-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala-Gly-c[Cys-Lys-Asn-c[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-Ser-Cys]) and AT6S (DOTA-Ala-Gly-c[Cys-Lys-c[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-Ser-Cys]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation.

Pitfalls in the Detection of Insulinomas With Glucagon-Like Peptide-1 Receptor Imaging.

Purpose: Physiological pancreaticoduodenal uptake of radiolabeled exendin-4 in Brunner glands of the proximal duodenum is the most common pitfall for false interpretation of glucagon-like peptide-1 receptor (GLP-1R) imaging. The aim of this study was to analyze the pancreaticoduodenal uptake in GLP-1R PET/CT and SPECT/CT images and to identify additional potential reading pitfalls in patients with suspected insulinoma.

Methods: A post hoc analysis of a prospective study, including 52 consecutive patients, was performed.

GIP receptor: Expression in neuroendocrine tumours, internalization, signalling from endosomes and structure-function relationship studies.

GIP is well known as a peptide regulating metabolic functions. In this review paper, we summarize a series of data on GIP receptor (GIPR). First, expression study of GIPR in human neuroendocrine tumours showed a very high incidence (nearly 100%) and a high density in both functional and non functional pancreatic tumours, ileal tumours, bronchial tumours and medullary thyroid carcinomas.

68Ga-Exendin-4 PET/CT Detects Insulinomas in Patients With Endogenous Hyperinsulinemic Hypoglycemia in MEN-1.

Context: Surgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size ≥20 mm. Functioning PanNETs, such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery.

Localization of Tc-GRP Analogs in GRPR-Expressing Tumors: Effects of Peptide Length and Neprilysin Inhibition on Biological Responses.

The overexpression of gastrin-releasing peptide receptors (GRPRs) in frequently occurring human tumors has provided the opportunity to use bombesin (BBN) analogs as radionuclide carriers to cancer sites for diagnostic and therapeutic purposes. We have been alternatively exploring human GRP motifs of higher GRPR selectivity compared to frog BBN sequences aiming to improve pharmacokinetic profiles. In the present study, we compared two differently truncated human endogenous GRP motifs: GRP(14⁻27) and GRP(18⁻27).

AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients.

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported.

The tetraamine chelator outperforms HYNIC in a new technetium-99m-labelled somatostatin receptor 2 antagonist.

Background: Somatostatin receptor targeting radiopeptides are successfully being used to image, stage, and monitor patients with neuroendocrine tumours. They are exclusively agonists that internalise upon binding to the relevant receptor. According to recent reports, antagonists may be preferable to agonists.

New Gastrin Releasing Peptide Receptor-Directed [Tc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation.

We have previously reported on the gastrin releasing peptide receptor (GRPR) antagonist [Tc]1, ([Tc]demobesin 1, Tc-[N'-diglycolate-dPhe,Leu-NHEt]BBN(6-13)). [Tc]1 has shown superior biological profile compared to analogous agonist-based Tc-radioligands. We herein present a small library of [Tc]1 mimics generated after structural modifications in (a) the linker ([Tc]2, [Tc]3, [Tc]4), (b) the peptide chain ([Tc]5, [Tc]6), and (c) the C-terminus ([Tc]7 or [Tc]8).

Safety, Biodistribution, and Radiation Dosimetry of Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study.

Preclinical and preliminary clinical evidence indicates that radiolabeled somatostatin (sst) receptor antagonists perform better than agonists in detecting neuroendocrine tumors (NETs). We performed a prospective phase I/II study to evaluate the sst receptor antagonist Ga-OPS202 (Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH)) for PET imaging. Here, we report the results of phase I of the study.

In Vitro Evaluation of Molecular Tumor Targets in Nuclear Medicine: Immunohistochemistry Is One Option, but Under Which Conditions?

The identification of new molecular targets for diagnostic and therapeutic applications using in vitro methods is an important challenge in nuclear medicine. One such method is immunohistochemistry, increasingly popular because it is easy to perform. This review presents the case for conducting receptor immunohistochemistry to evaluate potential molecular targets in human tumor tissue sections.

Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications.

Modern drug discovery highly depends on the identification and validation of the drug targets. Using the method of in vitro quantitative receptor autoradiography, we demonstrated that-for instance, in neuroendocrine tumors-up to 3 receptors can be coexpressed at a relatively high density. In addition, nonendocrine tumors such as breast, prostate, and brain tumors concomitantly express several G protein-coupled receptors at a high density.

A Critical Evaluation of sst3 and sst5 Immunohistochemistry in Human Pituitary Adenomas.

Background: Somatostatin receptor (sst) overexpression in neuroendocrine tumors allows sst-targeted tumor imaging and therapy with long-acting, cold, or radioactive somatostatin analogs. sst2 has been most important, owing to its wide overexpression and high affinity for somatostatin analogs, but other sst subtypes become of increasing clinical interest due to drug development. Immunohistochemistry is the preferred method to detect sst in resected tumor tissues.

PET/CT Imaging of Unstable Carotid Plaque with Ga-Labeled Somatostatin Receptor Ligand.

Ga-labeled somatostatin receptor ligand PET imaging has recently been shown in preclinical and early human studies to have a potential role in the evaluation of vulnerable arterial plaques. We prospectively evaluated carotid plaque Ga-DOTATATE uptake in patients with recent carotid events, assessed inter- and intraobserver variability of such measurements, and explored the mechanism of any plaque DOTATATE activity with immunohistochemistry in resected specimens. Twenty consecutively consenting patients with recent symptomatic carotid events (transient ischemic attack, stroke, or amaurosis fugax), due for carotid endarterectomy, were prospectively recruited.

Approaches to improve metabolic stability of a statine-based GRP receptor antagonist.

Unlabelled: The bombesin receptor family, in particular the gastrin-releasing peptide receptor (GRPr), is an attractive target in the field of nuclear oncology due to the high density of these receptors on the cell surface of several human tumors. The successful clinical implementation of Cu-CB-TE2A-AR06, Ga-RM2 and Ga-NODAGA-MJ9, prompted us to continue the development of GRPr-antagonists. The aim of the present study was to assess if N-terminal modulations of the statine-based GRPr-antagonist influence the binding affinity, the pharmacokinetic performance and the in vivo metabolic stability.

Highly Increased 125I-JR11 Antagonist Binding In Vitro Reveals Novel Indications for sst2 Targeting in Human Cancers.

Unlabelled: There is recent in vitro and in vivo evidence that somatostatin receptor subtype 2 (sst) antagonists are better tools to target neuroendocrine tumors (NETs) than sst agonists. Indeed, antagonists bind to a greater number of sst sites than agonists. Whether sst antagonists could be used successfully to target non-NETs, expressing low sst density, is unknown.

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers.

Unlabelled: The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, (125)I-Bolton-Hunter-Exendin(9-39)NH2 ((125)I-BH-Ex(9-39)NH2), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas.

Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer.

The gastrin-releasing peptide receptor (GRPr) is an important molecular target for the visualization and therapy of tumors and can be targeted with radiolabeled bombesin derivatives. The present study aims to develop statine-based bombesin receptor antagonists suitable for labeling with 64Cu for imaging by positron emission tomography (PET). The potent GRPr antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was conjugated to the sarcophagine (3,6,10,13,16,19-hexaazabicyclo[6.

Localization of Hidden Insulinomas with ⁶⁸Ga-DOTA-Exendin-4 PET/CT: A Pilot Study.

Unlabelled: (111)In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]exendin-4 ((68)Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas.

Methods: (68)Ga-DOTA-exendin-4 PET/CT and (111)In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order on 5 patients with endogenous hyperinsulinemic hypoglycemia.

Stereochemistry of amino acid spacers determines the pharmacokinetics of (111)In-DOTA-minigastrin analogues for targeting the CCK2/gastrin receptor.

The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L).

Neurotensin receptors in pancreatic ductal carcinomas.

Background: The frequent expression of neurotensin receptors (NT-R) in primaries of pancreatic ductal carcinomas has triggered the development of radioactive neurotensin analogs for possible in vivo targeting of these tumors. However, the complete lack of information regarding NT-R in liver metastases of pancreatic cancer and pancreatic intraepithelial neoplasia (PanIN) makes an in vitro study of NT-R in these tissues indispensable.

Methods: Using in vitro receptor autoradiography with (125)I-[Tyr(3)]-neurotensin, NT-R were investigated in 18 primaries and 23 liver metastases of pancreatic ductal carcinomas as well as in 19 PanIN lesions.

Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs.

Unlabelled: A high proportion of gut and bronchial neuroendocrine tumors (NETs) overexpresses somatostatin receptors, especially the sst2 subtype. It has also recently been observed that incretin receptors, namely glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors, can be overexpressed in gut and bronchial NETs. However, because not all tumors can express these receptors in sufficient amounts, in vivo imaging with a single radioligand may not always be successful.

Does somatostatin or gastric inhibitory peptide receptor expression correlate with tumor grade and stage in gut neuroendocrine tumors?

Background/aims: Important characteristics of neuroendocrine neoplasms (NEN) for prognosis and therapeutic decisions are the MIB-1 proliferative index (tumor grade) and tumor stage. Moreover, these tumors express peptide hormone receptors like somatostatin and gastric inhibitory peptide (GIP) receptors which represent important established and potential future targets, respectively, for molecular imaging and radiotherapy. However, the interrelation between tumor proliferation, stage, and peptide receptor amounts has never been assessed.