GRPR-Antagonists Carrying DOTAGA-Chelator via Positively Charged Linkers: Perspectives for Prostate Cancer Theranostics.

Gastrin-releasing peptide receptor (GRPR)-antagonists have served as motifs in the development of theranostic radioligands for prostate cancer. Our efforts have been focused on the development of radiolabeled RM26 (H-DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) analogs, such as [In]In-DOTAGA-PEG2-RM26. We recently showed that its Gly/Sar-substituted version, [In]In-AU-RM26-M1, resisted degradation by neprilysin (NEP) while in circulation and achieved higher tumor uptake in mice.

Preclinical evaluation of new GRPR-antagonists with improved metabolic stability for radiotheranostic use in oncology.

Background: The gastrin-releasing peptide receptor (GRPR) has been extensively studied as a biomolecular target for peptide-based radiotheranostics. However, the lack of metabolic stability and the rapid clearance of peptide radioligands, including radiolabeled GRPR-antagonists, often impede clinical application. Aiming at circumventing these drawbacks, we have designed three new GRPR-antagonist radioligands using [Tc]Tc-DB15 ([Tc]Tc-N-AMA-DIG-Phe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt; AMA: p-aminomethylaniline; DIG: diglycolate) as a motif, due to its high GRPR-affinity and stability to neprilysin (NEP).

Preclinical Evaluation of a Novel High-Affinity Radioligand [Tc]Tc-BQ0413 Targeting Prostate-Specific Membrane Antigen (PSMA).

Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl-triglutamate chelator for labeling with Tc-99m (designated as BQ0413).

Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry.

Introduction: Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression using computer modeling.

Preclinical Characterization of a Stabilized Gastrin-Releasing Peptide Receptor Antagonist for Targeted Cancer Theranostics.

Radiolabeled gastrin-releasing peptide receptor (GRPR) antagonists have shown great promise for the theranostics of prostate cancer; however, their suboptimal metabolic stability leaves room for improvements. It was recently shown that the replacement of Gly with Sar in the peptidic [D-Phe,Leu-NHEt,-Met]BBN(6-14) chain stabilized the [Tc]Tc-DB15 radiotracer against neprilysin (NEP). We herein present DOTAGA-PEG-(Sar)RM26 (AU-RM26-M1), after Gly to Sar-replacement.

Co-injection of anti-HER2 antibody Trastuzumab does not increase efficacy of [Lu]Lu-PSMA-617 therapy in an animal model of prostate cancer.

One novel option for treating metastatic castration resistant prostate cancer is radionuclide therapy targeting prostate-specific membrane antigen (PSMA), e.g. [Lu]Lu-PSMA-617.

The GRPR Antagonist [Tc]Tc-maSSS-PEG-RM26 towards Phase I Clinical Trial: Kit Preparation, Characterization and Toxicity.

Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [Tc]Tc-maSSS-PEG-RM26 (based on [D-Phe, Sta, Leu-NH]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models.

Phase I Trial of [Tc]Tc-maSSS-PEG-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [Tc]Tc-maSSS-PEG-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 µg of [Tc]Tc-maSSS-PEG-RM26 (600-700 MBq).

Preclinical Characterisation of PSMA/GRPR-Targeting Heterodimer [Ga]Ga-BQ7812 for PET Diagnostic Imaging of Prostate Cancer: A Step towards Clinical Translation.

The development of radioligands targeting prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) has shown promising results for the imaging and therapy of prostate cancer. However, studies have shown that tumors and metastases can express such targets heterogeneously. To overcome this issue and to improve protein binding, radioligands with the ability to bind both PSMA and GRPR have been developed.

Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules.

Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, Z-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. Z-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K 6 nM), and an even stronger affinity (K 0.

Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands.

Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617.

HER3 PET Imaging: Ga-Labeled Affibody Molecules Provide Superior HER3 Contrast to Zr-Labeled Antibody and Antibody-Fragment-Based Tracers.

HER3 (human epidermal growth factor receptor type 3) is a challenging target for diagnostic radionuclide molecular imaging due to the relatively modest overexpression in tumors and substantial expression in healthy organs. In this study, we compared four HER3-targeting PET tracers based on different types of targeting molecules in a preclinical model: the Zr-labeled therapeutic antibody seribantumab, a seribantumab-derived F(ab)-fragment labeled with Zr and Ga, and the Ga-labeled affibody molecule [Ga]Ga-Z. The novel conjugates were radiolabeled and characterized in vitro using HER3-expressing BxPC-3 and DU145 human cancer cells.

Ga-PET-imaging of GRPR-expression in prostate cancer: production and characterization of [Ga]Ga-NOTA-PEG-RM26.

Molecular imaging of the gastrin-releasing peptide receptor (GRPR) could improve patient management in prostate cancer. This study aimed to produce gallium-66 (T = 9.5 h) suitable for radiolabeling, and investigate the imaging properties of gallium-66 labeled GRPR-antagonist NOTA-PEG-RM26 for later-time point PET-imaging of GRPR expression.

Preclinical Evaluation of Tc-Labeled GRPR Antagonists maSSS/SES-PEG-RM26 for Imaging of Prostate Cancer.

Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced Tc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers.

Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) were radiolabeled with Tc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice.

Increasing thermal stability and improving biodistribution of VEGFR2-binding affibody molecules by a combination of in silico and directed evolution approaches.

The family of vascular endothelial growth factor (VEGF) ligands and their interactions with VEGF receptors (VEGFRs) play important roles in both pathological and physiological angiogenesis. Hence, agonistic and antagonistic ligands targeting this signaling pathway have potential for both studies on fundamental biology and for development of therapies and diagnostics. Here, we engineer VEGFR2-binding affibody molecules for increased thermostability, refolding and improved biodistribution.

Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer.

The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy.

Radionuclide Molecular Imaging of EpCAM Expression in Triple-Negative Breast Cancer Using the Scaffold Protein DARPin Ec1.

Efficient treatment of disseminated triple-negative breast cancer (TNBC) remains an unmet clinical need. The epithelial cell adhesion molecule (EpCAM) is often overexpressed on the surface of TNBC cells, which makes EpCAM a potential therapeutic target. Radionuclide molecular imaging of EpCAM expression might permit selection of patients for EpCAM-targeting therapies.

Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer-Optimization of the Affinity towards PSMA by Linker Modification in Murine Model.

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator.

Effect of a radiolabel biochemical nature on tumor-targeting properties of EpCAM-binding engineered scaffold protein DARPin Ec1.

Radionuclide-based imaging of molecular therapeutic targets might facilitate stratifying patients for specific biotherapeutics. New type of imaging probes, based on designed ankyrin repeat proteins (DARPins), have demonstrated excellent contrast of imaging of human epidermal growth factor type 2 (HER2) expression in preclinical models. We hypothesized that labeling approaches, which result in lipophilic radiometabolites (non-residualizing labels), would provide the best imaging contrast for DARPins that internalize slowly after binding to cancer cells.

Increase in negative charge of Ga/chelator complex reduces unspecific hepatic uptake but does not improve imaging properties of HER3-targeting affibody molecules.

Upregulation of the human epidermal growth factor receptor type 3 (HER3) is a common mechanism to bypass HER-targeted cancer therapy. Affibody-based molecular imaging has the potential for detecting and monitoring HER3 expression during treatment. In this study, we compared the imaging properties of newly generated Ga-labeled anti-HER3 affibody molecules (HE)-Z-DOTA and (HE)-Z-DOTAGA with previously reported [Ga]Ga-(HE)-Z-NODAGA.

Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer.

Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis.