title: Optimised labeling, preclinical and initial clinical aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides.
abstract: Medullary thyroid carcinoma (MTC) expresses CCK-2 receptors. (111)In-labeled DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2) (DOTA-MG11), DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH(2) (DOTA-CCK), and (99m)Tc-labeled N(4)-Gly-DGlu-(Glu)(5)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2) ((99m)Tc-Demogastrin 2) are analogs developed for CCK-2 receptor-targeted scintigraphy. All 3 radiolabeled analogs were selected on the basis of their high CCK-2 receptor affinity and their good in vitro serum stability, with in vitro serum t(1/2) values of several hours. Radiolabeling of DOTA-peptides with (111)In requires a heating procedure, typically in the range of 80 degrees -100 degrees C up to 30 min. Following this procedure with DOTA-MG11 resulted in a >98 % incorporation of (111)In, however, with a radiochemical purity (RCP) of <50 %. The decrease in RCP was found to be due to oxidation of the methionine residue in the molecule. Moreover, this oxidized compound lost its CCK-2 receptor affinity. Therefore, conditions during radiolabeling were optimised: labeling of DOTA-MG11 and DOTA-CCK with (111)In involved 5 min heating at 80 degrees C and led to an incorporation of (111)In of >98 %. In addition, all analogs were radiolabeled in the presence of quenchers to prevent radiolysis and oxidation resulting in a RCP of >90 %. All 3 radiolabeled analogs were i.v. administered to 6 MTC patients: radioactivity cleared rapidly by the kidneys, with no significant differences in the excretion pattern of the 3 radiotracers. All 3 radiolabeled analogs exhibited a low in vivo stability in patients, as revealed during analysis of blood samples, with the respective t(1/2) found in the order of minutes. In patient blood, the rank of radiopeptide in vivo stability was: (99m)Tc-Demogastrin 2 (t(1/2) 10-15 min)>(111)In-DOTA-CCK (t(1/2) approximately 5-10 min)>(111)In-DOTA-MG11 (t(1/2)<5 min).
authors.affiliation: Department of Nuclear Medicine, Erasmus MC Rotterdam's 3015 CE Rotterdam, The Netherlands. w.a.p.breeman@erasmusmc.nl
authors.forename: Wouter A P
authors.initials: WA
authors.lastname: Breeman
authors.forename: A C
authors.initials: AC
authors.lastname: Fröberg
authors.forename: E
authors.initials: E
authors.lastname: de Blois
authors.forename: A
authors.initials: A
authors.lastname: van Gameren
authors.forename: M
authors.initials: M
authors.lastname: Melis
authors.forename: M
authors.initials: M
authors.lastname: de Jong
authors.forename: T
authors.initials: T
authors.lastname: Maina
authors.forename: B A
authors.initials: BA
authors.lastname: Nock
authors.forename: J L
authors.initials: JL
authors.lastname: Erion
authors.forename: H R
authors.initials: HR
authors.lastname: Mäcke
authors.forename: E P
authors.initials: EP
authors.lastname: Krenning
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001345:Autoradiography; D018276:Carcinoma, Medullary / Q000000981:diagnostic imaging*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005260:Female; D005755:Gastrins / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008875:Middle Aged; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B / Q000032:analysis / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging*
chemical_list: D005755:Gastrins; D019275:Radiopharmaceuticals; D043887:Receptor, Cholecystokinin B; C008530:minigastrin