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There is an expanding body of evidence showing that synthetic peptides in combination with radioactive isotopes can be utilized for medical purposes. This area is of particular interest in oncology where applications in diagnosis and therapy are at different stages of development. We review the contributions in this area by the group originally founded by Carlo Pedone in Naples many years ago. We highlight the work of this group in the context of other developments in this area, focusing on three biologically relevant receptor systems: somatostatin, gastrin-releasing peptide, and cholecystokinin-2/gastrin receptors. We focus on key milestones, state of the art, and challenges in this area of research as well as the current and future outlook for expanding clinical applications., (© 2024 European Peptide Society and John Wiley & Sons Ltd.)

Targeting specific cell membrane markers for both diagnostic imaging and radionuclide therapy is a rapidly evolving field in cancer research. Some of these applications have now found a role in routine clinical practice and have been shown to have a significant impact on patient management. Several molecular targets are being investigated in ongoing clinical trials and show promise for future implementation. Advancements in molecular biology have facilitated the identification of new cancer-specific targets for radiopharmaceutical development., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Purpose: The extra-domain A1 of tenascin-C (TC-A1) is highly expressed in the extracellular matrix of tumours and on newly formed blood vessels and is thus a valuable target for radionuclide therapy. Tenarad is a fully human miniantibody or small immunoprotein (SIP, molecular weight 80 kDa) labelled with (131)I that is derived from a TC-A1-binding antibody. Previous phase I/II studies with a similar compound ((131)I-L19SIP) used for radioimmunotherapy (RIT) have shown preliminary efficacy in a variety of cancer types. In this ongoing phase I/II trial, Tenarad was administered to patients with recurrent Hodgkin's lymphoma (HL) refractory to conventional treatments., Methods: Eight patients (four men, four women; age range 19 - 41) were enrolled between April 2010 and March 2011. All patients had received a median of three previous lines of chemotherapy (range three to six) and seven had also undergone autologous stem cell transplantation (ASCT) or bone marrow transplantation. In addition, seven patients received external beam radiation. All patients had nodal disease, constitutional B symptoms and some showed extranodal disease in skeletal bone (four patients), lung (three), liver (two) and spleen (one). Baseline assessments included whole-body FDG PET with contrast-enhanced CT and diagnostic Tenarad planar and SPECT studies. Patients were considered eligible to receive a therapeutic dose of Tenarad (2.05 GBq/m(2)) if tumour uptake was more than four times higher than that of muscle., Results: All patients were eligible and received the therapeutic dose of Tenarad. Only one patient developed grade 4 thrombocytopenia and leucocytopenia, requiring hospitalization and therapeutic intervention. All other patients had haematological toxicity of grade 3 or lower, which resolved spontaneously. At the first response assessment (4 - 6 weeks after therapy), one patient showed a complete response, one showed a partial response (PR) and five had disease stabilization (SD). Five patients were given up to three repeated Tenarad treatments. One patient showed SD which then improved to a PR, three showed clinical benefit while maintaining SD and one patient showed disease progression., Conclusion: Tenarad RIT is effective in chemorefractory HL and resulted in objective responses or clinical benefit in the majority of patients. Toxicity was acceptable despite the high load of prior treatments, previous ASCT and multiple Tenarad administrations. Further studies are planned to define the most effective schedule for this type of RIT in HL patients.

The development of receptor targeting radiolabeled ligands has gained much interest in recent years for diagnostic and therapeutic applications in nuclear medicine. Cholecystokinin (CCK) receptors have been shown to be overexpressed in a subset of neuroendocrine and other tumors. We are evaluating binding and biodistribution properties of a CCK8 peptide derivative labeled with (99m)Tc(I)-tricarbonyl. The CCK8 peptide was modified at its N-terminus by adding to its N-terminus two lysine-histidine modules (KH), where histidine is coupled to the side chain of the lysine ((KH)(2)-CCK8). (99m)Tc(I)-tricarbonyl was generated with the IsoLinktrade mark kit. A431 cells stably transfected with a cDNA encoding for the human CCK2 receptor were utilized to determine binding affinity, internalization, and retention of the labeled peptide, in comparison with wild-type A431 cells. A nude mouse tumor model was obtained by generating A431-CCK2R and A431-control tumors in opposite flanks of the animals. High specific activity labeling with (99m)Tc was achieved. In A431-CCK2R cells, specific saturable binding was observed as well as evident internalization of the radiolabeled peptide after binding. Biodistribution experiments showed rapid, specific localization of (KH)(2)-CCK8 on A431-CCK2R xenografts compared with control tumors, although absolute uptake values were not markedly higher compared with background activity. Clearance of unbound radioactivity was both urinary and hepatobiliary. In imaging experiments, while targeting to CCK2R positive tumors could be appreciated, there was poor contrast between target and nontarget areas. (KH)(2)-CCK8 shows adequate in vitro and in vivo properties for CCK2R targeting although improvement of biodistribution warrant further development., ((c) 2008 Wiley Periodicals, Inc.)

Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with 111In or 99mTc for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with 111In and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both 111In-DTPAGlu-G-CCK8 and 99mTcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model. 111In-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. 99mTc-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.

Recent years have seen an increased effort in the development of peptide based radiopharmaceuticals for nuclear medicine applications in imaging and therapy. This field is of particular interest in the development of new cancer imaging and treatment strategies. Major developments in the molecular biology of cancer have brought forth the discovery of a number of receptor systems and other cell surface molecules that can be utilized as molecular targets for peptide based agents. Although such a strategy is very appealing and shows great potential for application in humans, there are as yet very few radiopharmaceuticals developed based on this scheme that have made it into clinical practice. Many different factors contribute to the generation of a successful radiopharmaceutical. Among these, a thorough and efficient pre-clinical evaluation process is necessary to single out those lead compounds that show more promise and are most likely to be winners in clinical applications. To maximize the efficacy of pre-clinical testing one must utilize currently available technology to the best extent possible. Expertise in different areas of drug development is indispensable for this type of research. This work will analyze currently available methods utilized to evaluate radiopharmaceuticals being developed, from compound design to evaluation in pre-clinical animal models.

Radiolabeled peptide-based formulations are being evaluated for their application in oncological imaging and therapy using nuclear medicine techniques. A major breakthrough in the field was the discovery and identification of the G-protein coupled receptor superfamily that are overexpressed in a variety of human cancers. These receptors act as targets for endogenous compounds, often of peptidic nature, which can be radiolabeled and, therefore, could potentially be utilized as radiopharmaceuticals. This general strategy has proven successful for application in humans in only a few cases thus far. However, the use of more sophisticated structural methodology to enhance our understanding of the interactions between the receptor and the endogenous peptide or its analogs, and a more efficient preclinical evaluation process, may help to single out the most promising compounds for further development and eventual use in the clinical application of radiopharmaceuticals. This review analyzes current methods of approaching these key points. The rational process for developing peptide-based radiopharmaceuticals is presented, from the structural analysis of the peptide-receptor interaction for the identification and modeling of the peptide analogs to the synthesis, with an appropriate metal carrier, of compounds that mimic endogenous peptides. Finally, the in vitro and in vivo biological testing and evaluation in preclinical animal models is described. To render the entire process successful, expertise in different areas of drug development is indispensable.