PET and SPECT Imaging of a Radiolabeled Minigastrin Analogue Conjugated with DOTA, NOTA, and NODAGA and Labeled with ⁶⁴Cu, ⁶⁸Ga, and ¹¹¹In

Abstract

Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either (68)Ga, (64)Cu, or (111)In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, (68)Ga- and (111)In-labeled peptides showed higher tumor-to-background ratios than the (64)Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for (111)In- and (68)Ga-labeled peptides. In contrast, the biodistribution of the (64)Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of (64)Cu from the chelator and subsequent transchelation to proteins. Based on the present study, (68)Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.

PET of EGFR with 64Cu‐cetuximab‐F(ab′)2 in mice with head and neck squamous cell carcinoma xenografts

“…However, this resulted in increased radioactivity levels in the liver, which was attributed to transchelation of Cu 2+ from DOTA to superoxide dismutase and ceruloplasmin (28). Previous reports have demonstrated the enhanced thermodynamic stability of Cu-triazamacrocyclic complexes compared with Cu-DOTA derivatives (29)(30)(31)(32)(33)(34)(35).…”

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

“…For many years, several other classes of theranostic radioligand systems have been in preclinical and clinical development for imaging or peptide receptor radionuclide therapy (in addition to the prominent radioiodine therapy approach). These include, among others, radiolabeled peptide analogs, such as the somatostatin receptor (SSTR) (57,58), cholecystokinin 2 receptor (gastrin receptor) (59,60), gastrin-releasing peptide receptor (GRPr) (61,62), glucagon-like peptide 1 receptor (63), and C-X-C motif chemokine receptor 4 (CXCR4) (64)(65)(66) ligands. So far, the SSTR, GRPr, and CXCR4 radioligands have been the most promising in clinical settings.…”

Radiolabeled theranostics: magnetic and gold nanoparticles

“…These imaging modalities are the most conventional imaging methods that depend on the radionuclides properties. 30 In the current study, we will provide important insights upon the radiolabeled NPs/NSs and will discuss their biomedical/pharmaceutical applications in relation with the imaging techniques used. …”