[111In-1,4,7,10-Tetraazacyclododecane- N, N', N'', N'''-tetraacetic acid-Pro1,Tyr4]Bombesin

Excerpt

[¹¹¹In-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Pro¹,Tyr⁴]Bombesin ([¹¹¹In-DOTA-Pro¹,Tyr⁴]BN) is a peptide analog of human gastrin-releasing peptide (GRP) conjugated with ¹¹¹In, and it was developed for single-photon emission computed tomography (SPECT) imaging of tumors with overexpressed GRP receptors (GRP-R) (1). ¹¹¹In is a gamma emitter with a physical half-life (t_½) of 2.8 days.

The amphibian bombesin (BBN or BN), a peptide of 14 amino acids, is an analog of human GRP, a peptide of 27 amino acids, and binds to GRP-R 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 in a number of tumor cell lines. The BN-R superfamily includes at least four different subtypes, namely the GRP-R subtype (BB2), the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype (8). 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, 6-9).

There have been varying degrees of success in the development of GRP-R–targeted radiopharmaceuticals for diagnostic or therapeutic applications (9). Various BN analogs have been labeled with ^99mTc and ¹¹¹In for SPECT imaging (13, 14). Despite some concern about the possible effect of BN to stimulate tumor growth, Breeman et al. (10) synthesized the BN-R agonist [¹¹¹In-DTPA-Pro¹,Tyr⁴]BN. The study reported that this agonist had a high specific localization in GRP-R–positive tissues and tumor. [¹¹¹In-DTPA-Pro¹,Tyr⁴]BN differs from native BN in that pGlu¹ is replaced by DTPA-Pro¹ and Leu⁴ is replaced by Tyr⁴. Breeman et al. (10) showed that this agonist was internalized by cells expressing GRP-R whereas the antagonist [¹¹¹In-DTPA-Tyr⁵,d-Phe⁶]BN(5-13)NHEt was not. In another study, Breeman et al. (1) used the more stable DOTA chelator to prepare [¹¹¹In-DOTA-Pro¹,Tyr⁴]BN.