Peptide radiopharmaceuticals in nuclear medicine

Abstract

This article reviews the labelling of peptides that are recognised to be of interest for nuclear medicine or are the subject of ongoing nuclear medicine research. Applications and approaches to the labelling of peptide radiopharmaceuticals are discussed, and drawbacks in their development considered.

[ 64 Cu-NOTA-8-Aoc-BBN(7-14)NH 2 ] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues

“…n recent years, nuclear medicine researchers have been investigating the potential of radiolabeled peptides to target selective receptors expressed on human tumor cancer cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Successful targeting of somatostatin receptor-positive tumors by receptor-specific diagnostic radiopharmaceuticals has pioneered efforts by others to develop new biologically active targeting vectors that have high affinity and selectivity for human tumors (1,2,11).…”

Molecular Imaging of Breast Cancer Tissue via Site-Directed Radiopharmaceuticals

“…As a consequence of these findings, research efforts have shifted towards the utilization of monoclonal antibodies, which have been designed to target specific antigens that are over-expressed on tumor cells (Signore et al, 2001). However, radiolabeled monoclonal antibodies have had limited clinical success due to several factors including the immunogenicity of the murine antibodies frequently employed in radiotracer preparation, the predominately hepatobiliary route of excretion, and the reduced ability to extravasate and access the target antigen as a result of the large size of intact monoclonal antibodies (Blok et al, 1999).Although the introduction of Fab´ and F(ab) 2´ fragments, chimeric, and humanized antibodies have diminished these effects, accumulation of monoclonal antibodies in tumor tissue continues to be insufficient, generating unfavorable target to background ratios.The advent of radiolabeled biologically active peptides in the early 1990s provided a means to overcome the limitations associated with these early radiopharmaceuticals (Table 1) (Fischman et al, 1993).The unique overexpression of specific receptors on malignant cells allows for their selective targeting using radiolabeled peptides that are designed to act as ligands for these receptors (Katzenellenbogen et al, 1995). A number of these receptor targets that are described herein rapid degradation by both aminopeptidases and endopeptidases, OctreoScan ® incorporates modified amino acids into the Phe-(D)Trp-Lys-Thr receptor binding motif of octreotide to inhibit its metabolism and allow for increased tumor uptake.…”

“…These factors have a significant impact on the tumor-to-background ratio, and hence the diagnostic and therapeutic utility that will be exhibited by a radiotracer. While the GRPr binding motif is not generally modified during conjugate production, amendments to this basic sequence are commonly employed for a number of reasons including augmentation of conjugate resistance to degradation by plasma peptidases, alteration of the pharmacokinetic properties of the derivative, and facilitation of the radiolabeling procedure (Blok et al, 1999;Signore et al, 2001). Incorporation of an inert spacer group into a BBN-based radiopharmaceutical is an effective method of modifying both the physiochemical properties and the metabolic fate of the bioconjugate, improving both the residualization of radioactivity by GRPr-positive malignant cells and clearance of the radiotracer from the blood and non-target tissues (Pomper & Gelovani, 2008).…”

“…Radiolabeling may result in substantial alterations to both the lipophilicity and the charge of the radiopharmaceutical and has important consequences for both the biodistribution and the kinetic properties of the resulting agent (Blok et al, 1999;Signore et al, 2001). For instance, the introduction of a negative charge at the N-terminus of a BBN analog leads to a loss of binding affinity, while a positive charge augments it, resulting in the potential for increased accumulation in GRPr rich tissues.…”

“…However, the type of complex formed and its stability are highly dependent on labeling conditions, which include pH, BFCA, reducing agent, and concentration. Initially, 99m Tc chemistry focused on the +5 oxidation state as it may be complexed using a broad range of thiol-, isonitrile-, or phosphine-containing chelates to produce compounds that are highly stable in aqueous media (Blok et al, 1999). However, it is often difficult to produce well-defined conjugates with high specific activity via direct or indirect radiolabeling techniques, due to the fact that the reduction of the disulfide bonds in the targeting vector or the ligand framework may occur as a consequence of the presence of excess reducing agent (Sn 2+ ) in the labeling cocktail (Schibli & Schubiger, 2002).…”