Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms

Abstract

Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.

Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

“…This is a unique and puzzling finding of utmost interest for this class of theranostic GPCR radioligands, and it can only be speculated that the described advantage of SSTR antagonists over SSTR agonists can be explained by factors such as the recognition of a larger number of binding sites by antagonists, slow dissociation of SSTR-bound antagonists, and delayed and slow internalization of antagonists (74).…”

[68Ga]Ga-DOTA-TOC: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging

“…However, if the density of somatostatin receptors is not sufficient, the lesions cannot be visualized by [ 68 Ga]Ga-DOTA-TOC [47]. An increased uptake of [ 68 Ga]Ga-DOTA-TOC is not specific for GEP-NETs and, therefore, the evaluation of disease-specific uptake is warranted [46,48]. As [ 68 Ga]Ga-DOTA-TOC is an agonist for SSTR, the tracer is internalized upon binding to the receptor [48].…”

“…Since the physical half-life of 68 Ga (67.7 min) is considerably lower than the elimination rate of the tracer, the biological half-life of the tracer will have little impact on the effective half-life of [ 68 Ga]Ga-DOTA-TOC. Effective half-lives of the tracer in liver and kidney are about 70 min and 75 min, respectively [48].…”

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

“…In addition, antagonists were reported to recognize a higher number of receptor‐binding sites compared with agonists, which resulted in higher tumor uptake and tumor retention of the radiolabeled antagonists in vivo . [ 203,204 ] Recently, a SSTR‐targeting antagonist was evaluated for PRRT in a pilot study on four cancer patients. [ 205 ] The absorbed radiation doses in the tumor and the tumor‐to‐kidney and tumor‐to‐bone marrow dose ratios were higher for the antagonistic compound compared with a SSTR agonist.…”