Tc-Ethylenediaminediacetic acid/hydrazinonicotinamide-[dGlu]minigastrin

Tc-Ethylenediaminediacetic acid/hydrazinonicotinamide-[dGlu]minigastrin (Tc-EDDA/HYNIC-MG0) is a radiolabeled peptide developed for single-photon emission computed tomography (SPECT) imaging of tumors that express the gastrin/cholecystokinin-2 (CCK-2) receptor (1). Tc is a gamma emitter with a physical half-life () of 6.01 h. The gastrointestinal peptides gastrin and CCK have various regulatory functions in the brain and gastrointestinal tract (2). Gastrin and CCK have the same COOH-terminal pentapeptide amide sequence, which is the biologically active site (3). Human gastrin is a peptide composed of 34 amino acids and also is found in several C-terminal truncated forms (4). These C-terminal truncated forms include the minigastrin, which is a 13-residue peptide with the sequence of LEEEEEAYGWMDF-NH. CCKs exist in a variety of biologically active molecular forms that are derived from a precursor molecule comprising 115 amino acids (5). These forms range from 4 to 58 amino acids in length and include sulphated and unsulphated CCK-8, which has the structure DYMGWMDF-NH. They bind to and act through transmembrane G-protein−coupled receptors (6). Two different CCK receptor subtypes have been identified in normal tissues. CCK-1 (CCK-A, alimentary) receptors have low affinity for gastrin, and CCK-2 (CCK-B, brain) receptors have high affinity for gastrin (5). They also differ in terms of molecular structure, distribution, and affinity for CCK. These receptors have also been found to be expressed or overexpressed on a multitude of tumor types (6). CCK-2 receptors have been found most frequently in medullary thyroid carcinomas, small-cell lung cancers, astrocytomas, and stromal ovarian cancers (2). CCK-1 receptors have been identified in gastroenteropancreatic tumors, meningiomas, and neuroblastomas. Reubi and Waser (7) designed a series of radiolabeled CCK-8 peptides that showed high specificity for potential imaging of tumors expressing CCK-2 receptors. de Jong et al. (8) developed a In-labeled nonsulfated CCK-8 analog using 1,4,7,10-tetraazacyclododecane--tetraacetic acid (DOTA) as a bifunctional chelating agent. The radioligand showed high specific internalization rates in the receptor-positive AR42J rat pancreatic tumor cells. Because of its favorable physical properties, Tc is still the radionuclide of choice for routine clinical applications (9). HYNIC is a bifunctional coupling agent for Tc-labeling of peptides that can achieve high specific activities without interfering with the amino acid sequence responsible for receptor binding (10-12). In this approach, Tc is bound to the hydrazine group, and other coordination sites are occupied by one or more coligands. The choice of coligand can influence the stability and hydrophilicity of the radiolabeled peptide. Using the HYNIC labeling strategy and EDDA or tris(hydroxymethyl)-methylglycine(tricine) as the coligand, von Guggenberg et al. (1) reported success in radiolabeling the MG0 peptide (d-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-PheNH). The Tc-EDDA/HYNIC-MG0 peptide showed high tumor uptake in nude mice bearing AR42J tumors. However, the very high kidney activity may limit its clinical applications.