PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64)Cu, (68)Ga, and (111)In.

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.
AuthorsS Roosenburg, P Laverman, L Joosten, M S Cooper, P K Kolenc-Peitl, J M Foster, C Hudson, J Leyton, J Burnet, W J G Oyen, P J Blower, S J Mather, O C Boerman, J K Sosabowski
JournalMolecular pharmaceutics (Mol Pharm) Vol. 11 Issue 11 Pg. 3930-7 (Nov 3 2014) ISSN: 1543-8392 [Electronic] United States
PMID24992368 (Publication Type: Journal Article)
Chemical References
  • 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
  • Acetates
  • Chelating Agents
  • Copper Radioisotopes
  • Gallium Radioisotopes
  • Gastrins
  • Heterocyclic Compounds
  • Heterocyclic Compounds, 1-Ring
  • Indium Radioisotopes
  • Peptides
  • Radiopharmaceuticals
  • Receptor, Cholecystokinin B
  • 1,4,7-triazacyclononane-N,N',N''-triacetic acid
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • minigastrin
  • Acetates (pharmacology)
  • Animals
  • Cell Line, Tumor
  • Chelating Agents (chemistry)
  • Copper Radioisotopes (chemistry)
  • Female
  • Gallium Radioisotopes (chemistry)
  • Gastrins (chemistry)
  • Heterocyclic Compounds (pharmacology)
  • Heterocyclic Compounds, 1-Ring (pharmacology)
  • Humans
  • Indium Radioisotopes (chemistry)
  • Inhibitory Concentration 50
  • Mice
  • Mice, SCID
  • Multimodal Imaging
  • Neoplasm Transplantation
  • Peptides (chemistry)
  • Positron-Emission Tomography
  • Radiopharmaceuticals (chemistry)
  • Receptor, Cholecystokinin B (metabolism)
  • Tomography, Emission-Computed, Single-Photon
  • Tomography, X-Ray Computed

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