Cholecystokinin-B/gastrin receptor binding peptides: Preclinical development and evaluation of their diagnostic and therapeutic potential

The high sensitivity of pentagastrin stimulation in detecting primary or me tastatic medullary thyroid cancer (MTC) suggests widespread expression of t he corresponding receptor type on human MTC. Indeed, autoradiographic studi es demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in >90% of MTCs but in a high percentage of small cell lung cancers and potentially a variety of gastrointestinal adenocarcinomas. In a pilot study, we have d emonstrated the feasibility of radiolabeled gastrin-I to target CCK-B recep tor-expressing tissues in vivo in animals and patients (T.M. Behr et al., F ur. J. Nucl. Med., 25: 424-430, 1998). The aim of the present study was to systematically optimize, in a preclinical model, suitable radioligands for targeting CCK-B receptors in vivo. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK-receptor binding tetrapeptide sequence Trp-Met -Asp-PheNH(2) or derivatives thereof, were studied. They were radioiodinate d by the Iodogen or Bolton-Hunter procedures. The peptides tested were memb ers of the gastrin- or cholecystokinin families or possessed characteristic s of both, which differ by the intramolecular position of a tyrosyl moiety (occurring in native or sulfated form). Their stability and affinity were s tudied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing s.c. human MTC xenografts. Diethylene-tri amine-pentaacetate derivatives of suitable peptides were synthesized, evalu ated, and labeled with In-111. All members of the CCK or gastrin family were stable in serum (with t1/2s o f several hours at 37 degrees C); nevertheless, the stability of those pept ides was highest that bore the NH2-terminal pGlu residues (e.g., big gastri n, gastrin-I, caerulein, and others) or D-amino acids. In accordance to the ir comparably low affinity, nonsulfated members of the CCK family showed fa irly low uptake in the tumor and other CCK-B receptor expressing tissues (e .g., the stomach). Sulfated CCK derivatives performed significantly better but additionally displayed a high uptake in normal, CCK-A receptor-expressi ng tissues (such as the liver/gallbladder, pancreas, and bowel). Best tumor uptake and tumor:nontumor ratios were obtained with members of the gastrin family, probably because of their selectivity and affinity for the CCK-B r eceptor subtype. Pilot therapy experiments in MTC bearing animals showed si gnificant antitumor efficacy as compared with untreated controls. In-111-La beled diethylene-triamine-pentaacetate derivatives of minigastrin showed ex cellent targeting of CCK-B receptor-expressing tissues in animals and a nor mal human volunteer. These data suggest that CCK/gastrin analogues may be a useful new class of receptor binding peptides for diagnosis and therapy of CCK-B receptor expre ssing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin de rivatives may be preferable because of their CCK-B receptor selectivity, an d hence, lower accretion in normal CCK-A receptor-expressing organs. Furthe r preclinical as well as clinical studies are ongoing.