Radiolabeled peptides for targeting cholecystokinin-B/gastrin receptor-expressing tumors

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 have demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung canc ers, some ovarian cancers, astrocytomas and potentially a variety of adenoc arcinomas. The aim of this study was to systematically screen and optimize, in a preclinical model and a pilot clinical study, suitable radioligands f or targeting CCK-B receptors in vivo. Methods: A variety of CCK/gastrin-rel ated peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH(2) or derivatives thereof, were studied. They w ere radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramole cular position of a tyrosyl moiety. Their stability and affinity were studi ed in vitro and in vivo; their biodistribution and therapeutic efficacy wer e tested in nude mice bearing subcutaneous human MTC xenografts, Diethylene triamine pentaacetic acid (DTPA) derivatives of suitable peptides were synt hesized successfully and their preclinical and initial clinical evaluations were performed, labeled with In-111. Results: All members of the CCK or ga strin families were stable in serum (with half-lives of several hours at 37 degrees C); nevertheless, the stability of those peptides bearing N-termin al pGlu residues or D-amino acids was significantly higher. In accordance w ith their comparably low affinity, nonsulfated members of the CCK family sh owed fairly low uptake in the tumor and other CCK-B receptor-expressing tis sues. Sulfated CCK derivatives performed significantly better but also disp layed a comparably high uptake in normal CCK-A receptor-expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtain ed with members of the gastrin family because of their selectivity and affi nity for the CCK-B receptor subtype. Pilot therapy experiments in MTC-beari ng animals showed significant antitumor efficacy compared with untreated co ntrols. DTPA derivatives of minigastrin were successfully developed. In a p ilot clinical study, radioiodinated and In-111-labeled derivatives showed e xcellent targeting of physiological CCK-B receptor-expressing organs, as we ll as all known tumor sites. Conclusion: CCK/gastrin analogs may be a usefu l new class of receptor-binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulf ated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, hence lower accretion in normal CCK-A receptor-expressing orga ns.