H<sub>2</sub><i>CHX</i>dedpa and H<sub>4</sub><i>CHX</i>octapaChiral Acyclic Chelating Ligands
for <sup>67/68</sup>Ga and <sup>111</sup>In Radiopharmaceuticals
Caterina F. Ramogida
Jacqueline F. Cawthray
Eszter Boros
Cara L. Ferreira
Brian O. Patrick
Michael J. Adam
Chris Orvig
10.1021/ic502942a.s003
https://acs.figshare.com/articles/dataset/H_sub_2_sub_i_CHX_i_dedpa_and_H_sub_4_sub_i_CHX_i_octapa_Chiral_Acyclic_Chelating_Ligands_for_sup_67_68_sup_Ga_and_sup_111_sup_In_Radiopharmaceuticals/2196379
The chiral acyclic ligands H<sub>2</sub><i>CHX</i>dedpa (N<sub>4</sub>O<sub>2</sub>), H<sub>2</sub><i>CHX</i>dedpa-bb (N<sub>4</sub>O<sub>2</sub>),
and H<sub>4</sub><i>CHX</i>octapa (N<sub>4</sub>O<sub>4</sub>) (<i>CHX</i> = cyclohexyl/cyclohexane, H<sub>2</sub>dedpa
= 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = <i>N</i>,<i>N</i>′-dibenzylated, H<sub>4</sub>octapa = <i>N</i>,<i>N</i>′-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-<i>N</i>,<i>N</i>′-diacetic acid) were synthesized,
complexed with Ga(III) and/or In(III), and evaluated for their potential
as chelating agents in radiopharmaceutical applications. The ligands
were compared to the previously studied hexadentate H<sub>2</sub>dedpa
and octadentate H<sub>4</sub>octapa ligands to determine the effect
adding a chiral 1<i>R</i>,2<i>R</i>-<i>trans</i>-cyclohexane to replace the ethylenediamine backbone would have on
metal complex stability and radiolabeling kinetics. It was found that
[Ga(<i>CHX</i>dedpa)]<sup>+</sup> showed very similar properties
to those of [Ga(dedpa)]<sup>+</sup>, with only one isomer in solution
observed by NMR spectroscopy, and minimal structural changes in the
solid-state X-ray structure. Like [Ga(dedpa)]<sup>+</sup>, [Ga(<i>CHX</i>dedpa)]<sup>+</sup> exhibited exceptionally high thermodynamic
stability constants (log <i>K</i><sub>ML</sub> = 28.11(8)),
and the chelate retained the ability to label <sup>67</sup>Ga quantitatively
in 10 min at room temperature at ligand concentrations of 1 ×
10<sup>–5</sup> M. In vitro kinetic inertness assays demonstrated
the [<sup>67</sup>Ga(<i>CHX</i>dedpa)]<sup>+</sup> complex
to be more stable than [<sup>67</sup>Ga(dedpa)]<sup>+</sup> in a human
serum competition, with 90.5% and 77.8% of <sup>67</sup>Ga remaining
chelate-bound after 2 h, respectively. Preliminary coordination studies
of H<sub>4</sub><i>CHX</i>octapa with In(III) demonstrated
[In(<i>CHX</i>octapa)]<sup>−</sup> to have an equivalently
high thermodynamically stable constant as [In(octapa)]<sup>−</sup>, with log <i>K</i><sub>ML</sub> values of 27.16(9) and
26.76(14), respectively. The [<sup>111</sup>In(<i>CHX</i>octapa)]<sup>−</sup> complex showed exceptionally high in
vitro kinetic inertness over 120 h in human serum, comparing well
with previously reported [<sup>111</sup>In(octapa)]<sup>−</sup> values, and an improved stability compared to the current industry
“gold standards” 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial
investigations reveal that the chiral acyclic hexadentate H<sub>2</sub><i>CHX</i>dedpa and octadentate H<sub>4</sub><i>CHX</i>octapa ligands are ideal candidates for radiopharmaceutical elaboration
of gallium or indium isotopes, respectively.
2015-02-16 00:00:00
hexadentate H 2 dedpa
2 h
67 Ga
log K ML values
chelating agents
inertness assays
10 min
H 4 octapa
stability constants
Initial investigations
label 67 Ga
octadentate H 4 octapa ligands
DOTA
log K ML
diethylenetriaminepentaacetic acid
ligand concentrations
h 2 CHX dedpa
chiral acyclic hexadentate H 2 CHX dedpa
radiolabeling kinetics
120 h
indium isotopes
H 4 CHX octapa
serum competition
DTPA
Preliminary coordination studies
chiral acyclic ligands H 2 CHX dedpa
NMR spectroscopy
octadentate H 4 CHX octapa ligands
ethylenediamine backbone
N 4 O 4
room temperature