In-Tetraazacyclododecane-,,,-tetraacetic acid-Asp–Tyr(SOH)–Met–Gly–Trp–Met–Asp–Phe–NH

The gastrointestinal peptides gastrin and cholecystokinin-2 (CCK2) have various regulatory functions in the brain and gastrointestinal tract (1). Gastrin and CCK2 have the same COOH-terminal pentapeptide amide sequence GWMDF-NH, which is the biologically active site (2). Human gastrin is a peptide composed of 33 amino acids and also exists in several C-terminal–truncated forms (3). These truncated forms include minigastrin (MG0), which is a 13-residue peptide with the sequence of d–Glu–Glu–Glu–Glu–Glu–Glu–Ala–Tyr–Gly–Trp–Met–Asp–Phe–NH. CCKs exist in a variety of biologically active molecular fragments ranging from 4 to 18 amino acids and including sulphated and unsulphated CCK8, which is an octapeptide (DYMGWMDF-NH) (4). Two CCK receptor subtypes have been identified in normal tissues by their binding affinities to gastrin. CCK1 (CCK-A, alimentary) receptors have low affinity for gastrin, and CCK2 (CCK-B, brain) receptors have high affinity for gastrin (4). The sulphated CCK8 peptide displays high affinity for both CCK1 and CCK2 receptors, which are G-protein–coupled (5). These receptors have also been found to be overexpressed in a variety of tumor types (5). CCK2 receptors have been found most frequently in medullary thyroid carcinomas, small-cell lung cancers, astrocytomas, and stromal ovarian cancers (1). CCK1 receptors have been identified in gastroenteropancreatic tumors, meningiomas, and neuroblastomas. Radiolabeled CCK8 peptides have been studied in tumors expressing CCK2 receptors with good specificity for potential imaging. Hellmich et al. (6) discovered a splice variant version (CCK2i4svR) of the CCK-2 receptor, which is expressed constitutively in human colorectal and pancreatic cancer (7, 8). A sulfated pan-CCKR-binding peptide, Asp–Tyr(SOH)–Met–Gly–Trp–Met–Asp–Phe–NH2 (sCCK8), was N-terminally conjugated with tetraazacyclododecane-,,,-tetraacetic acid (DOTA) for radiolabeling with InCl to form In-DOTA-sCCK8 for imaging CCK2R and CCK2i4svR expressing tumors (9).