In-Tetraazacyclododecane-,,,-tetraacetic acid-dihistidine-norleucine peptide analog

In-Tetraazacyclododecane-,,,-tetraacetic acid-dihistidine-norleucine peptide (In-DOTA-H2-Nle) is a radiolabeled gastrin analog that can be used for single-photon emission computed tomography (SPECT) imaging of tumors that express the gastrin/cholecystokinin-2 (CCK-2) receptor (1). In is a gamma emitter with a physical half-life () of 2.8 days. 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 exists in several C-terminal–truncated forms (1). These C-terminal–truncated forms include 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 (4). 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 (5). 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 (4). They also differ in terms of molecular structure, distribution, and affinity for CCK. These receptors have also been found to be expressed or overexpressed in a multitude of tumor types (5). 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 et al. (6) 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. (7) developed an In-labeled unsulphated CCK8 analog that used 1,4,7,10-tetraazacyclododecane--tetraacetic acid (DOTA) as a bifunctional chelating agent. The radioligand showed high specific internalization rates in receptor-positive rat pancreatic AR42J tumor cells. von Guggenberg et al. (8) reported the synthesis of Tc-hydrazinonicotinic acid (HYNIC)-minigastrin complexes and high tumor uptake in nude mice bearing AR42J tumors. Nock et al. (9) prepared Tc-labeled minigastrin analogs and found that they displayed high specific localization in nude mice bearing AR42J tumors. Mather et al. (1) synthesized a library of different peptide sequences based on the C-terminal sequences of CCK-8 or minigastrin. These peptides were labeled with In by DOTA or diethylene triamine pentaacetic acid (DTPA) conjugation. The dihistidine analog In-DOTA-H2-Nle was evaluated to study the effect of substituting a norleucine (Nle) residue for the methionine (Met) residue near the C-terminus. The study appeared to show that this substitution could result in a reduction in tumor uptake of the radiopeptide analog.