177Lu-DOTA-Gly-4-aminobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

Excerpt

Bombesin (BBN) is a tetradecapeptide isolated from the European fire-bellied frog (Bombina bombina) (1). BBN possesses a specific C-terminus (Gly-His-Leu-Met), which is necessary for its biological activity (2). Several peptides that are structurally related to BBN have been identified in mammals. Gastrin-releasing peptide (GRP) is a peptide of 27 amino acids from porcine gastric tissues with Gly-His-Leu-Met at its C-terminus. Neuromedin B (NMB) is a peptide of 32 amino acids from porcine spinal cords with Gly-His-Phe-Met at its C-terminus. These peptides are the ligands of a group of receptors called BBN receptors (BB-R). The mammalian BB-R family consists of three subtypes, including the GRP-preferring receptor (GRP-R or BB₂-R (384 amino acids)), the NMB-preferring receptor (NMB-R or BB₁-R (390 amino acids)), and an orphan receptor (BB₃-R (399 amino acids)) (3). These subtypes of BB-R are overexpressed in various diseased tissues. For example, GRP acts as a neurotransmitter and an endocrine cell-growth factor to regulate various functions of gastrointestinal and central nervous systems and to stimulate cell proliferations in lung, colon, stomach, pancreas, breast, and prostate cancers in humans (4). GRP binds to GRP-R as an agonist and is subsequently transported to the perinuclear space via receptor-mediated endocytosis (1), which leads to an accumulation in GRP-R–positive tissues. Thus, tagging GRP with an imaging probe allows for assessment of GRP-R in vivo.

¹⁷⁷Lu-(4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetracetic acid (DOTA))-Gly-4-aminobenzoyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH₂ (¹⁷⁷Lu-AMBA) is used with single-photon emission computed tomography (SPECT) imaging of GRP-R (5). ¹⁷⁷Lu-AMBA consists of two components: a peptide of eight amino acids that is composed of the seven common amino acids in the C-terminus of BBN/GRP (Trp-Ala-Val-Gly-His-Leu-Met) and a complex of ¹⁷⁷Lu-DOTA attached to the N-terminus of the peptide via a glycyl-4-aminobezoic acid linker. The small peptide accounts for the biological potency and possesses many advantages such as high in vivo stability, high uptake in tumors, low uptake in non-target tissues, and a rapid clearance from blood via the kidney (3). ¹⁷⁷Lu is a radionuclide from the group of rare earth radionuclides, and it is produced by neutron bombardment of purified target material in reactors (6). With a half-life of 6.71 days for β^- emission at 498 keV and 78% branch fraction, ¹⁷⁷Lu has been a very promising radionuclide in radiotherapy for effective destruction of small tumors and metastasis (optimal size 1.2–3.0 mm) while sparing normal tissue (7). ¹⁷⁷Lu also emits low-energy gamma rays at 208 and 113 keV with 10% and 6% abundance, respectively, which allows for direct monitoring of the activity distribution with SPECT and subsequent dosimetry calculations. ¹⁷⁷Lu-AMBA is currently under phase I clinical trials (8).