99mTc-Ethylenenediamine- N, N'-diacetic acid/hydrazinonicotinamide[Lys3]-bombesin

Excerpt

^99mTc-Ethylenediamine-N,N’-diacetic acid/hydrazinonicotinamide-[Lys³]-bombesin (^99mTc-EDDA/HYNIC-[Lys³]-BN) is a peptide analog of human gastrin-releasing peptide (GRP) conjugated with ^99mTc, and it was developed for planar gamma and single-photon emission computed tomography (SPECT) imaging of tumors with overexpressed GRP receptors (GRP-R) (1). ^99mTc is a gamma emitter with a physical half-life (t_½) of 6.02 h.

The amphibian bombesin (BBN or BN), a peptide of 14 amino acids, is an analog of human GRP, a peptide of 27 amino acids, that binds to GRP-R (BB2) with high affinity and specificity (2, 3). Both GRP and BN share an amidated C-terminus sequence homology of seven amino acids, -Trp-Ala-Val-Gly-His-Leu-Met-NH₂. BN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system (4, 5). They also act as potential growth factors for both normal and neoplastic tissues. Specific BN receptors (BN-R) have been identified in CNS and GI tissues and a number of tumor cell lines. The BN-R superfamily includes at least four different subtypes, namely the GRP-R subtype, the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype (6). Overexpression of GRP-R in various human tumors (e.g., breast, prostate, lung, colon, ovarian, and pancreatic cancers) provides opportunities to image tumors with the use of specific molecular imaging agents designed to target the GRP-R (3, 7-10).

There have been varying degrees of success in the current development of GRP-R–targeted radiopharmaceuticals for diagnostic or therapeutic applications (10). Various BN analogs have been labeled with ^99mTc and ¹¹¹In for SPECT imaging (1, 11-13). Baidoo et al. (12) synthesized and radiolabeled [Lys³]-BN (Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH₂) with ^99mTc through the diaminedithiol (DADT) bifunctional chelating agent. The ^99mTc-DADT-[Lys³]-BN showed high in vitro affinity to the BN-R in rat brain membrane preparations. Because of its favorable physical properties, ^99mTc is the radionuclide of choice for routine clinical applications of SPECT imaging (14). 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 (15-17). 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 (15, 18). Convenient freeze-dried kit formulations with HYNIC for labeling peptides with ^99mTc have been achieved (19). Using the HYNIC labeling strategy and EDDA/N-tris(hydroxymethyl)-methylglycine (tricine) as the coligands, Ferro-Flores et al. (1) successfully prepared ^99mTc-EDDA/HYNIC-[Lys³]-BN as a potential molecular imaging probe for GRP-R.