99mTc-Ethylenediaminediacetic acid/hydrazinonicotinic acid-[ d Glu1, desGlu2–6]minigastrin

Excerpt

^99mTc-Ethylenediaminediacetic acid/hydrazinonicotinic acid-[dGlu¹, desGlu^2–6]minigastrin (^99mTc-EDDA/HYNIC-MG11) 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). ^99mTc is a gamma emitter with a physical half-life (t_½) 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 exists in several C-terminal truncated forms (4). These C-terminal truncated forms include minigastrin, which is a 13-residue peptide with the sequence of LEEEEEAYGWMDF-NH₂. 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-NH₂. 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 carcinoma, small-cell lung cancers, astrocytomas, and stromal ovarian cancers (2). CCK-1 receptors have been identified in gastroenteropancreatic tumors, meningiomas, and neuroblastoma.

Reubi et al. (7) designed a series of radiolabeled CCK-8 peptides that showed high specificity for potential in vivo imaging of tumors expressing CCK-2 receptors. Because of its favorable physical properties, ^99mTc is still the radionuclide of choice for routine clinical applications (8). Hydrazinonicotinic acid (HYNIC) is a bifunctional coupling agent for ^99mTc labeling of peptides that can achieve high specific activities without interfering with the amino acid sequence responsible for receptor binding (9-11). In this approach, ^99mTc 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 ethylenediaminediacetic acid (EDDA) or tris(hydroxymethyl)-methylglycine (tricine) as the coligand, von Guggenberg et al. (12) reported the success of radiolabeling the MG0 peptide (d-Glu-Glu₅-Ala-Tyr-Gly-Trp-Met-Asp-PheNH₂). The ^99mTc-EDDA/HYNIC-MG0 peptide showed high tumor uptake in nude mice bearing AR42J tumors, but it also has very high kidney activity. To minimize kidney uptake, the same research group designed a shortened peptide analog by depletion of the five glutamic acid molecules in positions 2–6 to produce ^99mTc-EDDA/HYNIC-[dGlu¹, desGlu^2–6]minigastrin (^99mTc-EDDA/HYNIC-MG11) (1).