Tumour uptake of the radiolabelled somatostatin analogue [DOTA(0),TYR3]octreotide is dependent on the peptide amount

Radiolabelled tumour receptor-binding peptides can be used for in vivo scin tigraphic imaging. Recently, the somatostatin analogue [Tyr(3)]octreotide ( D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelat or DOTA (tetra-azacyclododecanetetra-acetic acid), enabling stable radiolab elling with both the high-energy beta particle-emitter yttrium-90 and the A uger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in v itro and in vivo (rat) experiments with these radiolabelled compounds showe d favourable binding and biodistribution characteristics with high uptake a nd retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA(0),T yr(3)]octreotide in somatostatin receptor subtype 2 (sst(2))-positive rat p ancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of In-111-labelled [DOTA(0),Tyr(3)]octreotide in normal, i.e. non-tumour-bear ing, and CA20948 tumour-bearing rats. This was done in order to find the am ount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simulta neously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA(0),Tyr(3)]octreotide in sst(2)-positive organs show ed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0.1 (pituitary and stomach) and 0.25 (pan creas) mu g. Uptake in the tumour was highest at 0.5 mu g injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [In-111-DTPA(0)]octreotide (D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Cys )-Thr(ol), DTPA = diethylene-triamine-pentaacetic acid), consistent with th e higher receptor affinity of the first compound. Our observations of mass- dependent differences in uptake of radiolabelled [DOTA(0),Tyr(3)]octreotide , being the resultant of a positive effect of increasing amounts of peptide on, for example, receptor clustering and a negative effect of receptor sat uration, are of consequence for rat radionuclide therapy studies with radio labelled peptides and may also be of consequence for human radionuclide the rapy studies with this compound.