4 research outputs found
New Macrobicyclic Chelator for the Development of Ultrastable <sup>64</sup>Cu-Radiolabeled Bioconjugate
Ethylene cross-bridged cyclam with two acetate pendant
arms, ECB-TE2A,
is known to form the most kinetically stable <sup>64</sup>Cu complexes.
However, its usefulness as a bifunctional chelator is limited because
of its harsh radiolabeling conditions. Herein, we report new cross-bridged
cyclam chelator for the development of ultrastable <sup>64</sup>Cu-radiolabeled
bioconjugates. Propylene cross-bridged TE2A (PCB-TE2A) was successfully
synthesized in an efficient way. The CuÂ(II) complex of PCB-TE2A exhibited
much higher kinetic stability than ECB-TE2A in acid decomplexation
studies, and also showed high resistance to reduction-mediated demetalation.
Furthermore, the quantitative radiolabeling of PCB-TE2A with <sup>64</sup>Cu was achieved under milder conditions compared to ECB-TE2A.
Biodistribution studies strongly indicate that the <sup>64</sup>Cu
complexes of PCB-TE2A cleared out rapidly from the body with minimum
decomplexation
New Bifunctional Chelator for <sup>64</sup>Cu-Immuno-Positron Emission Tomography
A new
tetraazamacrocyclic bifunctional chelator, TE2A-Bn-NCS, was
synthesized in high overall yield from cyclam. An extra functional
group (NCS) was introduced to the <i>N</i>-atom of TE2A
for specific conjugation with antibody. The Cu complex of TE2A-Bn-NCS
showed high kinetic stability in acidic decomplexation and cyclic
voltammetry studies. X-ray structure determination of the Cu-TE2A-Bn-NH<sub>2</sub> complex confirmed octahedral geometry, in which copper atom
is strongly coordinated by four macrocyclic nitrogens in equatorial
positions and two carboxylate oxygen atoms occupy the elongated axial
positions. Trastuzumab was conjugated with TE2A-Bn-NCS and then radiolabeled
with <sup>64</sup>Cu quantitatively at room temperature within 10
min. Biodistribution studies showed that the <sup>64</sup>Cu-labeled
TE2A-Bn-NCS-trastuzumab conjugates maintain high stability in physiological
conditions, and NIH3T6.7 tumors were clearly visualized up to 3 days
by <sup>64</sup>Cu-immuno-positron emission tomography imaging in
animal models
Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable <sup>64</sup>Cu-Based Radiopharmaceuticals
<i>N</i>-mono/dimethylated
TE2A tetraazamacrocycles (MM-TE2A
and DM-TE2A) were synthesized in high yields. Both Cu-MM/DM-TE2A complexes
showed increased kinetic stability compared to that of Cu-TE2A, whereas
Cu-DM-TE2A showed even higher in vitro stability than that of Cu-ECB-TE2A.
MM-TE2A and DM-TE2A were quantitatively radiolabeled with <sup>64</sup>Cu ions and showed rapid clearance from the body to emerge as a potential
efficient bifunctional chelator
Synthesis and Evaluation of New Generation Cross-Bridged Bifunctional Chelator for <sup>64</sup>Cu Radiotracers
Bifunctional chelators have been
successfully used to construct <sup>64</sup>Cu-labeled radiopharmaceuticals.
Previously reported chelators with cross-bridged cyclam backbones
have various essential features such as high stability of the copperÂ(II)
complex, high efficiency of radiolabeling at room temperature, and
good biological inertness of the radiolabeled complex, along with
rapid body clearance. Here, we report a new generation propylene-cross-bridged
chelator with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P)
developed with the aim of combining these key properties in a single
chelator. The PCB-TE1A1P was synthesized from cyclam with good overall
yield. The CuÂ(II) complex of our chelator showed good robustness in
kinetic stability evaluation experiments, such as acidic decomplexation
and cyclic voltammetry studies. The CuÂ(II) complex of PCB-TE1A1P remained
intact under highly acidic conditions (12 M HCl, 90 °C) for 8
d and showed quasi-reversible reduction/oxidation peaks at −0.77
V in electrochemical studies. PCB-TE1A1P was successfully radiolabeled
with <sup>64</sup>Cu ions in an acetate buffer at 60 °C within
60 min. The electrophoresis study revealed that the <sup>64</sup>Cu-PCB-TE1A1P
complex has net negative charge in aqueous solution. The biodistribution
and in vivo stability study profiles of <sup>64</sup>Cu-PCB-TE1A1P
indicated that the radioactive complex was stable under physiological
conditions and cleared rapidly from the body. A whole body positron
emission tomography (PET) imaging study further confirmed high in
vivo stability and fast clearance of the complex in mouse models.
In conclusion, PCB-TE1A1P has good potential as a bifunctional chelator
for <sup>64</sup>Cu-based radiopharmaceuticals, especially those involving
peptides