Cu-1,4,7-Triazacyclononane-1,4-diacetic acid (NO2A)-6-aminohexanoic acid (6-Ahx)-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH (BBN(7–14)NH), abbreviated as Cu-NO2A-(6-Ahx)-BBN(7–14)NH, is a bombesin (BBN)-based, Cu-NO2A-conjugated peptide that was synthesized by Lane et al. for use in positron emission tomography (PET) of tumors expressing gastrin-releasing peptide receptor (GRPR) (1, 2). GRPR is a glycosylated G-protein–coupled receptor that is normally expressed in non-neuroendocrine tissues of the breast and pancreas and in neuroendocrine cells of the brain, gastrointestinal tract, lung, and prostate (3, 4). GRPR has been found to be overexpressed in various human tumors, and a large number of BBN analogs have been investigated for GRPR-targeted imaging and therapy (5, 6). These analogs have been synthesized on the basis of either truncated BBN (BBN(6–14) or BBN(7–14)) or full-length BBN(1–14) (7, 8). Chelators and spacers have been used frequently for chelating metals and for improving the kinetics of conjugates (9-11). Cu is a radiometal with potential applications in diagnostic and therapeutic nuclear medicine. The half-life for Cu ( = 12.7 h) is long enough for drug preparation, quality control, imaging, and therapy (12, 13). However, use of Cu is limited by issues of transchelation to proteins found in blood and liver (such as superoxide dismutase) (1). A variety of chelators have been investigated for the purpose of stably chelating Cu (13). In general, Cu-labeled 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (Cu-DOTA) and Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (Cu-TETA) exhibit high uptake and retention in nontarget organs, which limits their application. Cross-bridged (CB) analogs, such as CB-DO2A ((1,4,7,10-tetraazabicyclo[5.5.2]tetradecane-4,10-diyl)diacetic acid), CB-TE2A ((1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl)diacetic acid), SarAr (1--(4-aminobenzyl)-3,6,10,13,16,19-hexa-aza-bicyclo-[6.6.6]eichosane-1,8-diamine), and NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), demonstrate improved copper containment by enhancing the ligand's rigidity (2, 14). Prasanphanich et al. recently reported that the NOTA-based Cu-NOTA-8-Aoc-BBN(7–14)NH conjugate (where 8-Aoc = 8-aminooctanoic acid) exhibited decreased accumulation in hepatic tissue as compared with other chelator-based (DOTA, TETA, and CB-TE2A) conjugates (2, 14). To improve the tumor uptake and maintain the good pharmacokinetic properties of the Cu-NOTA-8-Aoc-BBN(7–14)NH conjugate, Lane et al. synthesized a new group of conjugates with the NOTA derivative NO2A and replaced the spacer 8-Aoc with an aliphatic or aromatic linking (1). These conjugates were abbreviated as Cu-NO2A-(X)-BBN(7–14)NH, where X denotes the pharmacokinetic modifier, such as AMBA (para-aminobenzoic acid), β-Ala (beta-alanine), 5-Ava (5-aminovaleric acid), 6-Ahx, 8-Aoc, and 9-Anc (9-aminonanoic acid). The β-Ala, 5-Ava, 6-Ahx, and 9-Anc are aliphatic pharmacokinetic modifiers, ranging from three to nine carbons in length, whereas AMBA is an aromatic pharmacokinetic modifier and is more rigid than the aliphatic modifiers. Evidence indicates that a spacing moiety, ranging from three to eight carbons in length, can assist in receptor-mediated uptake (15). Conjugates containing an aromatic linker have significantly higher uptake and retention in PC-3 tumor tissue than those containing hydrocarbon or ether linkers (15, 16). Studies by Lane et al. have shown that the spacer X in the Cu-NO2A-(X)-BBN(7–14)NH conjugates has a significant role in clearance, accumulation, and retention of the conjugates in tumor tissue (1). The four conjugates showing the most favorable pharmacokinetic properties and the highest degree of pancreas and tumor accumulation were those in which X = 6-Ahx, 8-Aoc, 9-Anc, or AMBA. PET imaging with these conjugates produced high-contrast images of PC-3 tumor xenografts in severe combined immunodeficient (SCID) mice (1). This chapter describes the data obtained with Cu-NO2A-(6-Ahx)-BBN(7–14)NH. Detailed information for other Cu-NO2A-(X)-BBN(7–14)NH conjugates is available in MICAD (http://www.ncbi.nlm.nih.gov/books/NBK5330/) (1).
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