title: 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.
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.
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Roosenburg
authors.forename: P
authors.initials: P
authors.lastname: Laverman
authors.forename: L
authors.initials: L
authors.lastname: Joosten
authors.forename: M S
authors.initials: MS
authors.lastname: Cooper
authors.forename: P K
authors.initials: PK
authors.lastname: Kolenc-Peitl
authors.forename: J M
authors.initials: JM
authors.lastname: Foster
authors.forename: C
authors.initials: C
authors.lastname: Hudson
authors.forename: J
authors.initials: J
authors.lastname: Leyton
authors.forename: J
authors.initials: J
authors.lastname: Burnet
authors.forename: W J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: P J
authors.initials: PJ
authors.lastname: Blower
authors.forename: S J
authors.initials: SJ
authors.lastname: Mather
authors.forename: O C
authors.initials: OC
authors.lastname: Boerman
authors.forename: J K
authors.initials: JK
authors.lastname: Sosabowski
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003301:Copper Radioisotopes / Q000737:chemistry*; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry*; D005755:Gastrins / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D064847:Multimodal Imaging; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry; D043887:Receptor, Cholecystokinin B / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D002614:Chelating Agents; D003301:Copper Radioisotopes; D005710:Gallium Radioisotopes; D005755:Gastrins; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D043887:Receptor, Cholecystokinin B; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C008530:minigastrin; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid
keywords: CCK2R peptide; Cu-64; DOTA; Ga-68; In-111; NODAGA; NOTA; PET imaging; macrocyclic chelator