Preclinical evaluation of gastrin derivatives labelled with ¹¹¹In: Radiolabelling, affinity profile and pharmacokinetics in rats

Abstract

Background. Cholecystokinin receptor subtype 2 (CCK-2) is overexpressed in various tumours like medullary thyroid carcinomas and small cell lung cancer. Radiolabelled peptides that bind with high affinity and specificity to CCK-2 receptors, thus hold great potential for visualizing such tumours. Methods. We compared four 111 In labelled gastrin analogues, called minigastrins (MG), namely MG11, MG45, MG47 and MG48 linked to metal chelating DOTA in preclinical experiments. The radiolabelled peptides were tested for peptide binding in CCK-2 receptor-bearing cell line AR42J and for their pharmacokinetics in normal rats. Results. The experiments suggest that all gastrin analogues had similar and relatively rapid internalization into AR42J cells. Binding to CCK-2 receptors in AR42J cells was saturable for all agents but there were some differences in receptor affinity. This biodistribution study in rats showed a rapid decrease in blood radioactivity, predominantly renal clearance and saturable uptake of the radiopharmaceutical and/or its metabolites in the CCK-2 receptor-positive stomach. Higher kidney accumulation of radioactivity was only found for In-DOTA-MG11 are the most promising.

Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting

“…Based on the similar cell uptake of 111 In-DOTA-MGS1 and 111 In-DOTA-MGS4 in this cell line, we could directly compare the influence of stabilization on the targeting properties for these two radioligands. For both investigated radiopeptides, a very low unspecific uptake below 1% IA/g was observed in most tissues except kidney, the main excretory organ, and stomach, an organ with physiological CCK2R expression 43 . Only a very limited excretion may additionally occur through feces 20 , 43 .…”

“…For both investigated radiopeptides, a very low unspecific uptake below 1% IA/g was observed in most tissues except kidney, the main excretory organ, and stomach, an organ with physiological CCK2R expression 43 . Only a very limited excretion may additionally occur through feces 20 , 43 . As expected, 111 In-DOTA-MGS1, based on its low enzymatic resistance, showed a low tumor uptake of ~3% IA/g at 1 h p.i.…”

The importance of the gastrorenal axis in the control of body sodium homeostasis

“…Among the radiolabeled analogues of several enterokines (CCK, gastrin, bombesin, neurotensin, and somatostatin), gastrin is taken up and retained to the greatest extent by renal proximal tubules (100–1000-fold), presumably by reabsorption from the glomerular filtrate (Melis et al, 2005, Melicharova et al, 2014). Thus, gastrin levels in the kidney after feeding may be in the nanomolar range, concentrations we have used to study the ability of gastrin to inhibit NHE3 and Na + , K + -ATPase activities in human renal proximal tubule cells (Li & Jose, 2013, Li et al, 2016).…”

“…The normal fasting plasma gastrin levels range from 100 to 200 pg ml -1 ; the meal-stimulated blood gastrin concentration is about 2-to 4.5-fold higher, equivalent to a concentration of about 400 pM (Saqui-Salces et al 2012;Li et al 2014). Among the radiolabelled analogues of several enterokines (CCK, gastrin, bombesin, neurotensin and somatostatin), gastrin is taken up and retained to the greatest extent by renal proximal tubules (100to 1000-fold), presumably by reabsorption from the glomerular filtrate (Melis et al 2005;Melicharova et al 2014). Thus, gastrin levels in the kidney after feeding may be in the nanomolar range, concentrations we have used to study the ability of gastrin to inhibit the Na + -H + exhanger 3 and Na + -K + -ATPase activities in human renal proximal tubule cells (Li & Jose, 2013;Liu et al 2016).…”

Gastrorenal Axis

“…However, the natriuresis following ingestion of a critical amount of sodium may be due to the secretion of the enterokine gastrin by G-cells in the stomach and duodenum and released into the circulation (26, 35). Gastrin is reabsorbed by renal cortical tubules to a greater extent than the other enterokines released after a meal (34, 36). Once taken up by the kidney, gastrin then acts on its receptor, the CCK type B receptor, CCKBR, expressed in several nephron segments (35, 37, 38, 39) to decrease sodium transport.…”