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[en] Among the CCK-B receptor agonists reported to date, the two modified peptides BC 264 and BC 254 display a high affinity and selectivity for this binding site and are highly protected from enzymatic degradation. Recently, we reported the biological properties of a tritiated analog of this agonist, [3H]pBC 264, which fullfils all the criteria required for in vitro as well as in vivo studies of the CCK-B receptor. On the other hand, BC 254 displays a high affinity for the CCK-B binding sites in the guinea-pig (Ki = 0.56 nM) while its affinity in the rat is more than 60-fold lower, a difference which could be due to the occurrence of CCK-B receptor subtypes. In the present paper, we report the synthesis of [3H]pBC 264 and of the new tritiated ligand [3H]pBC 254 using [3H] NPS (N-succinimidyl[2,3-3H]propionate) as labelling agent. These two probes have high specific activity (70-100 Ci/mmol) and will enable extensive studies of the CCK-B receptors to be carried out. (author)
[en] Cholecystokinin subtype 2 receptors (CCK2R) are over expressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [111In-DOTA]MG11 ([(111In-DOTA)DGlu10]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients.
[en] Until now, few groups reported the antifreeze activity of cyclic glycopeptides; however, the tedious synthetic procedure is not amenable to study the intensive structure activity relationship. A series of N-linked cyclic glycopeptoids and glycopeptide have been prepared to evaluate antifreeze activity as a function of peptide backbone cyclization and methyl stereochemical effect on the rigid Thr position. This study has combined the cyclization protocol with solid phase peptide synthesis and obtained significant quantities of homogeneous cyclic glycopeptide and glycopeptoids. Analysis of antifreeze activity revealed that our cyclic peptide demonstrated RI activity while cyclic glycopeptoids showed no RI activity. These results suggest that the subtle changes in conformation and Thr orientation dramatically influence RI activity of N-linked glycopeptoids
[en] A specific radioimmunoassay was developed to the predicted nine amino acid C-terminal flanking peptide of cholecystokinin (peptide serine serine, PSS). In aqueous extracts of rat brain, PSS was undetectable unless the extracts were first treated with arylsulphatase, which also resulted in desulphation of cholecystokinin. The reverse-phase HPLC analysis of partially desulphated extracts showed the presence of two peaks intermediate to the naturally occurring and the completely desulphated forms. It is therefore proposed that the CCK-flanking peptide PSS has both tyrosine residues sulphated. (Auth.)
[en] Renal intracellular and brush border membranes were purified from rats injected with [35S]methionine. Solubilized transpeptidase (γGT) was immunoprecipitated and analyzed by SDS-polyacrylamide gel electrophresis (PAGE). The initial precipitates contain 3 bands corresponding to the core glycosylated propeptide (75K) and the mature heterodimer subunits (50K and 30K). The propeptide represents 75% of the radioactivity in γGT from 5 to 45 min postinjection consistent with cotranslational cleavage of 25% of the propeptide to subunits. By 20 min postinjection all three bands are more diffuse and endoglycosidase H-resistant. Between 20 and 30 min postinjection, propeptide and heterodimer coincidentally reach the brush border membrane. Propeptide then rapidly disappears (t/sub 1/2/ < 1 h) whereas heterodimer accumulates for 4 h then disappears with a t/sub 1/2/ of 2.5 d. The basis for these two distinct subcellular sites of γGT propeptide cleavage is unknown. Both purified γGT heterodimer and immunoprecipitates of labeled γGT occasionally exhibit high M/sub r/ bands (85K and 100K) on SDS-PAGE. Individual subunits and high M/sub r/ species were eluted from SDS gel slices, subjected to SDS-PAGE and analyzed on immunoblots with IgG affinity-purified against individual subunits. The cumulative data show that the subunits can form both stable homodimers (60K and 100K) and heterodimers (85K) during SDS-PAGE. Thus, these high M/sub r/ species do not represent biosynthetic intermediates of γGT