The overexpression of cholecystokinin subtype 2 receptors (CCK2Rs) in a variety of human tumors has provided the rationale for the development of radiolabeled CCK2R-specific ligands for diagnostic purposes. Native gastrin and cholecystokinin (CCK) have served as motifs for the development of numerous anti-CCK2R radiotracers. Typically, coupling of a suitable chelator at the peptide N-terminus, either directly or through a spacer, has allowed for stable binding of a clinically relevant diagnostic radiometal. Accordingly, gamma emitters (e.g., technetium-99m, or indium-111) have been considered for single photon emission tomography (SPECT) and positron emitters (e.g., gallium-68, or copper-64) for positron emission tomography (PET) in the detection of CCK2R-rich tumor lesions in patients. The anti-CCK2R radioligands developed for such purposes have been screened in preclinical studies using cells and animal models and attractive candidates were identified for further evaluation in patients with CCK2R-positive tumors.
Several studies on CCK2R-specific radioligands have revealed a common shortcoming of gastrin-based analogs, namely high accumulation of radioactivity in the kidneys. This behavior was attributed to the penta-Glu sequence in the native peptide chain and the favorably low kidney accumulation of truncated des-penta-Glu analogs has corroborated this hypothesis. However, all truncated analogs were rapidly hydrolyzed in the biological milieu failing to achieve reasonable tumor targeting. Several efforts to overcome the problem of fast enzymatic degradation of this type of radioligands have been adopted. On one hand, structural modifications have been pursued, such as substitution of the penta-Glu by the penta-DGlu chain, key amino acid replacements, cyclization or exchange of cleavable peptide bonds. Recently, an alternative smart approach was put to the test, involving the co-administration of inhibitors against the proteases directly implicated in the breakdown of injected gastrin/CCK-like radioligands. This simple approach led to significant enhancements of tumor uptake without unfavorably increasing renal values.
The successful shift of paradigm from receptor agonists to antagonists in the development of somatostatin and bombesin radioligands has triggered the search for radiolabeled CCK2R-antagonists as well. Hence, the first peptidomimetic-based radioligands with an antagonist profile at the CCK2R were recently reported showing attractive pharmacokinetics in animal models. Another exciting innovative methodology toward higher in vivo targeting of gastrin/CCK radiotracers has been the upregulation of CCK2R-expression on tumor sites via biochemical means.
In this chapter, advances in the diagnostic imaging of CCK2R-positive tumors with the advent of new tracers will be discussed. Significant progress made in previous years will be highlighted and recent innovations expected to have a clinical impact soon will be commented.
