Ga-Labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Tyr-cyclo(DAB-Arg-cyclo(Cys-Phe-d-Trp-Lys-Thr-Cys))

The Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Tyr-cyclo(DAB-Arg-cyclo(Cys-Phe-d-Trp-Lys-Thr-Cys)), abbreviated as Ga-AM3, is a somatostatin (SST)-based, bicyclic peptide conjugate developed by Fani et al. for SST receptor (SSTR)–targeted imaging of neuroendocrine tumors (1). The human SSTR family is a group of G-protein–coupled receptors with five members (SSTR1–SSTR5). All receptor members have seven α-helical transmembrane domains and possess a highly conserved sequence motif (YANSCANPI/VLY) in the seventh topology, which serves as a signature sequence for this family (2-4). Overall, there is 39%–57% sequence identity among the members, with the highest homology between SSTR1 and SSTR4, and among SSTR2, SSTR3, and SSTR5, respectively. The two groups of receptors also differ in their interactions with SST and its analogs (3-6). SSTR2, SSTR3, and SSTR5 have a high affinity for octreotide and seglitide, whereas SSTR1 and SSTR4 exhibit a very low affinity for them. With the exception of SSTR2, the precise contributions of other members remain to be elucidated. This is largely due to the lack of highly selective ligands and the co-expression of different members in single cells. SSTRs are distributed widely in cells both in the nervous system and periphery, and they have been shown to be overexpressed in a large number of malignancies, with particularly high density in neuroendocrine tumors (2, 7, 8). As the targets of SST radiopharmaceuticals, SSTRs are of considerable clinical relevance for tumor imaging and radionuclide therapy (2, 9, 10). Because the native SST has a very short biological half-life (<2 min), various analogs have been synthesized, including a group of bicyclic peptides. Bicyclic peptides were first synthesized to understand the bioactive conformation and pharmacophoric amino acid sequence, and to increase the metabolic stability of the natural peptide SST-14 (also known as somatotropin release-inhibiting factor (SRIF)-14) by increasing the rigidity of bicyclic peptides (11, 12). Thereafter, various modified bicyclic peptides have been synthesized and have exhibited higher potency and longer duration of biological activity than SRIF-14 (1, 11, 12). As seen in the structure of the lead peptide cyclo(Aha,cyclo(Cys-Phe-d-Trp-Lys-Thr-Cys)), conformational constraints are introduced by head-to-tail coupling of a 16-atom ring with 7-aminoheptanoic acid (Aha) to the N- and C-terminally amino acid–deleted octreotide. To identify metabolically stable pansomatostatin analogs, a group of investigators from Switzerland have generated a set of bicyclic peptides by forming a second 16-atom ring with Arg and γ-aminobutyric acid (GABA) while keeping the octreotide 20-atom sequence as an inner circle (13-15). These modifications led to the development of another lead peptide, cyclo(Arg-cyclo(Cys-Phe-d-Trp-Lys-Thr-Cys)-GABA), which is named HR3005 (1). Arg has been shown to be important for broad binding to SSTR subtypes, and GABA can be exchanged with diaminobutyric acid (DAB) for chelator coupling. Based on the HR3005 sequence, four bicyclic analogs have been further synthesized by Fani et al. from the same group (1). The influence of the conformational constraints on receptor binding profiles and the pharmacokinetics of the respective radiopeptides have been investigated. Studies by Fani et al. have shown that the high rigidity of these bicyclic radiopeptides leads to agonistic ligands with good affinity for all five SSTRs (1). The pharmacokinetic data of the DOTA-conjugated bicyclic peptide AM3 (DOTA-Tyr-cyclo(DAB-Arg-cyclo(Cys-Phe-d-Trp-Lys-Thr-Cys))) make it an excellent candidate for use as an imaging radiotracer (1).