64Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH2: a heterodimeric targeting vector for positron emission tomography imaging of prostate cancer.
BACKGROUND
The present study describes the design and development of a new heterodimeric RGD-bombesin (BBN) agonist peptide ligand for dual receptor targeting of the form (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2) in which Cu-64=a positron emitting radiometal; NO2A=1,4,7-triazacyclononane-1,4-diacetic acid; Glu=glutamic acid; 6-Ahx=6-aminohexanoic acid; RGD=the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide that has been used extensively to target α(v)β(3) receptors up-regulated on tumor cells and neovasculature; and BBN(7-14)NH(2)=Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH(2), an agonist analogue of bombesin peptide for specific targeting of the gastrin-releasing peptide receptor (GRPr).


METHODS
RGD-Glu-6-Ahx-BBN(7-14)NH(2) was manually coupled with NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), and the resulting conjugate was labeled with (64)Cu to yield (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2). Purification was achieved via reversed-phase high-performance liquid chromatography and characterization confirmed by electrospray ionization-mass spectrometry.


RESULTS
Competitive displacement binding assays displayed single-digit nanomolar IC(50) values showing very high binding affinities toward the GRPr for the new heterodimeric peptide analogues. In vivo biodistribution studies showed high uptake and retention of tumor-associated radioactivity in PC-3 tumor-bearing rodent models with little accumulation and retention in nontarget tissues. The radiolabeled conjugate also exhibited rapid urinary excretion and high tumor-to-background ratios. Micro-positron emission tomography (microPET) molecular imaging investigations produced high-quality, high-contrast images in PC-3 tumor-bearing mice 15 h postinjection.


CONCLUSIONS
Based on microPET imaging experiments that show high-quality, high-contrast images with virtually no residual gastrointestinal radioactivity, this new heterodimeric RGD-BBN conjugate can be considered as a promising PET tracer candidate for the diagnosis of GRPr-positive tumors in human patients.
Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
Andrew B
AB
Jackson
Prasant K
PK
Nanda
Tammy L
TL
Rold
Gary L
GL
Sieckman
Ashley F
AF
Szczodroski
Timothy J
TJ
Hoffman
Xiaoyuan
X
Chen
Charles J
CJ
Smith
D015119:Aminocaproic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000819:agonists / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000493:pharmacokinetics*; D003301:Copper Radioisotopes; D018698:Glutamic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018004:Receptors, Bombesin / Q000378:metabolism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
C519451:1,4,7-triazacyclononane-1,4-diacetate; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C118536:bombesin (7-14); D018698:Glutamic Acid; C047981:arginyl-glycyl-aspartic acid; D001839:Bombesin; D015119:Aminocaproic Acid