Optimised labeling, preclinical and initial clinical. aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides

Medullary thyroid carcinoma (MTC) expresses CCK-2 receptors. In-111-labeled DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2, (DOTA-MG11), DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2 (DOTA-CCK), and Tc-99m-labeled N-4-Gly-DGlu-(Glu)(5)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (Tc-99m-Demogastrin 2) are analogs developed for CCK-2 receptor-targeted scintigraphy. All 3 radiolabeled analogs were selected oil the basis of their high CCK-2 receptor affinity and their good in vitro scrum stability, with in vitro serum t(1/2) values of Several hours. Radiolabeling of DOTA-peptides with In-111 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 In-111, however, with a radiochemical purity (RCP) of <50 %. file 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 In-111 involved 5 min heating at 80 degrees C and led to an incorporation of In-111 of >99 %. 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: Tc-99m-Demogastrin 2 (t(1/2) 10-15 min)>In-111-DOTA-CCK (t(1/2) approximate to 5-10 min)> In-111-DOTA-MG11 (t(1/2)<5 min). (c) 2009 Elsevier Inc. All rights reserved.