64Cu-1,4,7-Triazacyclononane-1,4-diacetic acid-para-aminobenzoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

Excerpt

⁶⁴Cu-1,4,7-Triazacyclononane-1,4-diacetic acid (NO2A)-para-aminobenzoic acid (AMBA)-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH₂ (BBN(7–14)NH₂), abbreviated as ⁶⁴Cu-NO2A-(AMBA)-BBN(7–14)NH₂, is a bombesin (BBN)-based, ⁶⁴Cu-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).

⁶⁴Cu is a radiometal with potential applications in diagnostic and therapeutic nuclear medicine. The half-life for ⁶⁴Cu (t_1/2 = 12.7 h) is long enough for drug preparation, quality control, imaging, and therapy (12, 13). However, use of ⁶⁴Cu is limited by issues of in vivo 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 ⁶⁴Cu (13). In general, ⁶⁴Cu-labeled 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (⁶⁴Cu-DOTA) and ⁶⁴Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (⁶⁴Cu-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-N-(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 ⁶⁴Cu-NOTA-8-Aoc-BBN(7–14)NH₂ 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 ⁶⁴Cu-NOTA-8-Aoc-BBN(7–14)NH₂ 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 ⁶⁴Cu-NO2A-(X)-BBN(7–14)NH₂, where X denotes the pharmacokinetic modifier, such as AMBA, β-Ala (beta-alanine), 5-Ava (5-aminovaleric acid), 6-Ahx (6-aminohexanoic acid), 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 ⁶⁴Cu-NO2A-(X)-BBN(7–14)NH₂ conjugates has a significant role in clearance, accumulation, and retention of the conjugates in tumor tissue (1). ⁶⁴Cu-NO2A-(AMBA)-BBN(7–14)NH₂ exhibited the highest accumulation in tumor tissue and the most efficient clearance from whole-body tissues via the renal–urinary excretion pathway. PET imaging with ⁶⁴Cu-NO2A-(AMBA)-BBN(7–14)NH₂ produced high-contrast images of PC-3 tumor xenografts in severe combined immunodeficient (SCID) mice (1). This chapter describes the data obtained with ⁶⁴Cu-NO2A-(AMBA)-BBN(7–14)NH₂. Detailed information for other ⁶⁴Cu-NO2A-(X)-BBN(7–14)NH₂ conjugates is available in MICAD (http://www.ncbi.nlm.nih.gov/books/NBK5330/).