Hexadentate bispidine derivatives as versatile bifunctional chelate agents for copper(II) radioisotopes.

Abstract

The preparation and use of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonane) as chelate ligands for radioactive copper isotopes for diagnosis (64Cu) or therapy (67Cu) are reported. Starting from the hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand 1 with a keto and two ester substituents, the corresponding mono-ol 2 and two dicarboxylic acid derivatives 3 and 5 have been synthesized. A range of techniques, including single-crystal X-ray structure analysis, UV/vis spectroscopy, cyclic voltammetry, thin-layer- (TLC), and high-performance liquid chromatography (HPLC), have been used to characterize the structure and stability of the copper(II)-bispidine complexes. A rapid formation (within 1 min) of stable copper(II)-bispidine complexes under mild conditions (ambient temperature, aqueous solution) has been observed. Challenge experiments of these complexes in the presence of a high excess of competing ligands, such as glutathione, cyclam, or superoxide dismutase (SOD), as well as in rat plasma, gave no evidence of demetalation or transchelation. The bifunctional bispidine derivative 5 can be readily functionalized with biologically active molecules at the pendant carboxylate groups. The coupling of a bombesin analogue betahomo-Glu-betaAla-betaAla-[Cha(13),Nle(14)]BBN(7-14), by condensation of a carboxylate of the bispidine backbone with the N-terminus of the peptide produced the bifunctional ligand 6. The radiocopper(II) complex of this bombesin-bispidine conjugate has a considerable hydrophilicity (log D(o/w) < -2.4), and this leads to a very fast blood clearance (blood: 0.28 +/- 0.02 SUV, 1 h p.i.), low liver tissue accumulation (liver: 1.20 +/- 0.27 SUV, 1 h p.i.), and rapid renal-urinary excretion (kidneys: 6.06 +/- 2.96 SUV, 1 h p.i.) as shown by biodistribution studies of 64Cu-6 in Wistar rats. Preliminary in vivo studies of 64Cu-6 in NMRI nu/nu mice, bearing the human prostate tumor PC-3 showed an accumulation of the conjugate in the tumor (2.25 +/- 0.13 SUV, 12.5 min p.i.; 0.94 +/- 0.05 SUV, 55 min p.i.) and allowed a clear visualization of the gastrin-releasing peptide receptor distribution by positron emission tomography (PET).

• Authors: Stefanie Juran, Martin Walther, Holger Stephan, Ralf Bergmann, Jörg Steinbach, Werner Kraus, Franziska Emmerling, Peter Comba
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 20 Issue 2 Pg. 347-59 (Feb 2009) ISSN: 1520-4812 [Electronic] United States
• PMID: 19173600 (Publication Type: Journal Article)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Chelating Agents
• Copper Radioisotopes
• Cross-Linking Reagents
• Dicarboxylic Acids
• Ligands
• Pyridines
• Receptors, Bombesin
• bispidine
• pyridine
• Bombesin

Topics

• Animals
• Bombesin (metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacokinetics)
• Chelating Agents (chemistry)
• Copper Radioisotopes (chemistry)
• Cross-Linking Reagents (chemistry)
• Dicarboxylic Acids (chemistry)
• Gene Expression Regulation, Neoplastic
• Humans
• Kinetics
• Ligands
• Male
• Mice
• Positron-Emission Tomography
• Prostatic Neoplasms (diagnostic imaging, genetics, metabolism, pathology)
• Pyridines (chemistry)
• Radiochemistry
• Rats
• Receptors, Bombesin (metabolism)
• Tissue Distribution