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. 2022 Oct 31;61(43):17059-17067.
doi: 10.1021/acs.inorgchem.2c01992. Epub 2022 Oct 17.

Bn2DT3A, a Chelator for 68Ga Positron Emission Tomography: Hydroxide Coordination Increases Biological Stability of [68Ga][Ga(Bn2DT3A)(OH)]

Thomas W Price  1   2   3 , Isaline Renard  2   3 , Timothy J Prior  4 , Vojtěch Kubíček  5 , David M Benoit  6 , Stephen J Archibald  2   3 , Anne-Marie Seymour  2 , Petr Hermann  5 , Graeme J Stasiuk  1
Affiliations

Bn2DT3A, a Chelator for 68Ga Positron Emission Tomography: Hydroxide Coordination Increases Biological Stability of [68Ga][Ga(Bn2DT3A)(OH)]

Thomas W Price et al. Inorg Chem. .

Abstract

The chelator Bn2DT3A was used to produce a novel 68Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. Bn2DT3A complexes Ga3+ in a hexadentate manner, forming a mer-mer complex with log K([Ga(Bn2DT3A)]) = 18.25. Above pH 5, the hydroxide ion coordinates the Ga3+ ion following dissociation of a coordinated amine. Bn2DT3A radiolabeling displayed a pH-dependent speciation, with [68Ga][Ga(Bn2DT3A)(OH)]- being formed above pH 5 and efficiently radiolabeled at pH 7.4. Surprisingly, [68Ga][Ga(Bn2DT3A)(OH)]- was found to show an increased stability in vitro (for over 2 h in fetal bovine serum) compared to [68Ga][Ga(Bn2DT3A)]. The biodistribution of [68Ga][Ga(Bn2DT3A)(OH)]- in healthy rats showed rapid clearance and excretion via the kidneys, with no uptake seen in the lungs or bones.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthesis of Bn2DT3A and Subsequent Complexation of Ga3+. (a) (i) EtOH, Benzaldehyde, Reflux. (ii) NaBH4, 0 °C. (b) MeCN, Na2CO3, tert-Butyl Bromoacetate, 60 °C. (c) DCM, TFA. 0 °C to RT. (d) H2O, GaCl3, pH 4, Reflux
Figure 1
Figure 1
Molecular structure of [Ga(Bn2DT3A)] determined by X-ray crystallography. Hydrogen atoms have been omitted for clarity. Colors: gallium (pale brown); carbon (gray); nitrogen (blue); oxygen (red).
Figure 2
Figure 2
Speciation of Ga3+ in solution with Bn2DT3A. (T = 25 °C, I = 0.1 M NMe4Cl, [Bn2DT3A] = 4 mM, [Ga3+] = 2 mM).
Figure 3
Figure 3
Calculated energy of water molecule (blue) and hydroxide anion (green) interacting with [Ga(Bn2DT3A)] at various Ga–O distances.
Figure 4
Figure 4
(A) Radio-HPLC of [68Ga][Ga(Bn2DT3A)(OH)]− following semipreparative HPLC purification. (B) Stability of [68Ga][Ga(Bn2DT3A)(OH)]− to FBS assessed by radio-TLC. (i) Isolated species. (ii) After 30 min incubation in FBS. (iii) After 120 min incubation. (C) Radio-HPLC of [68Ga][Ga(Bn2DT3A)] following semipreparative HPLC purification. (D) Stability of [68Ga][Ga(Bn2DT3A)] to FBS assessed by radio-TLC. (i) Isolated species. (ii) After 30 min incubation in FBS. (E) Radio-TLC of [68Ga][GaCl3] incubated with FBS.
Figure 5
Figure 5
Effect of common reaction parameters on the radiolabeled products of [68Ga][GaCl3] and Bn2DT3A as assessed by radio-HPLC. (A) Effect of pH. [Bn2DT3A] = 100 μM. T = 25 °C. I = 0.1 M NaxH3–xPO4. t = 15 min. (B) Effect of ligand concentration. T = 25 °C. I = PBS. pH = 7.4. t = 15 min. (C) Effect of temperature. [Bn2DT3A] = 100 μM. I = PBS. pH = 7.4. t = 5 min. (D) Effect of reaction time. [Bn2DT3A] = 100 μM. T = 25 °C. I = PBS. pH = 7.4.
Figure 6
Figure 6
PET scans of healthy Sprague-Dawley rats injected with either [68Ga][Ga(Bn2DT3A)(OH)]− (top two rows) or [68Ga][Ga(Citrate)]− (bottom two rows) at indicated time points. Subsequent CT scan provided for co-registration of signal.
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