Tc-Hydrazinonicotinic acid-cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Phe-NH

The gastrointestinal peptides gastrin and cholecystokinin-2 (CCK2) have various regulatory functions in the brain and gastrointestinal tract (1). Both peptides 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, including sulphated and unsulphated CCK8, which is an octapeptide (Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-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. A cyclized minigastrin analog, cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Phe-NH (cyclo-MG1), for the gastrin receptor was -terminally conjugated with hydrazinonicotinic acid (HYNIC) for radiolabeling with Tc and ethylenediamine--diacetic acid (EDDA as a coligand to form Tc-HYNIC-cyclo-MG1 (6), which has been evaluated for imaging tumors expressing CCK2 receptors.