Crystal structure of aqua(2-{[2-({2-[bis(carboxylato-κO-methyl)amino-κN]ethyl}(carboxylato-κO-methyl)amino-κN)ethyl](carboxymethyl)azaniumyl}acetato)gallium(III) trihydrate

The structure of a GaIII complex compound with pentetic acid is reported. The complex molecule is a zwitterion and the GaIII centre is bound in a slightly distorted octahedral coordination sphere by two amine N atoms, three carboxylate O atoms and one water O atom.


Chemical context
The use of gallium-68 ( 68 Ga) for molecular imaging of diseases has become increasingly popular and the number of 68 Garelated articles has increased drastically in the past 10 years, as pointed out by Velikyan (2014). The application span is wide and covers the diagnosis of cancer, cardiovascular disease, infection and inflammatory conditions (Brasse & Nonat, 2015;Jalilian & Akhlaghi, 2013;Banerjee & Pomper, 2013;Schultz et al., 2013). The increase in popularity and use can be ascribed to several factors. On the one hand, 68 Ga produces highquality PET images. On the other hand, it has a half-life of 68 min, which makes it suitable for use in patients as the radiation dose can be kept at a minimum (Hofman & Hicks, 2016). 68 Ga can be eluted from a 68 Ge/ 68 Ga generator multiple times a day, which makes it easy for hospitals to prepare gallium solutions for patients on demand. It is vital that gallium ions are complexed, as free ions may cause undesirable effects in vivo. First, free gallium can cause iron release from transferrin, which may cause free-radical toxicity. Second, gallium ions may cause an additional and unnecessary radiation dose. 2-(Bis{2-[bis(carboxymethyl)amino]ethyl}amino)acetic acid (pentetic acid or DTPA) is an aminopolycarboxylic acid consisting of a diethylenetriamine backbone with five carboxy groups. A complex is easily formed between gallium and DTPA and it has a stability constant of 10 23.32 , which makes the complex stable against exchange with transferrin (Moerlein & Welch, 1981;Green & Welch, 1989). DTPA-peptides labelled with 68 Ga have been used for liverfunction imaging, determination of low-density lipoprotein ISSN 2056-9890 metabolism, bone-marrow function and molecular identification of metastatic tumours (Haubner et al., 2013;Moerlein et al., 1991;Vera et al., 2012;Pitalú a-Corté s et al., 2017), but the molecular structure of our compound has not yet been reported. Here we present and describe the molecular structure of the title compound (Fig. 1).

Structural commentary
The complex molecule (abbreviated as Ga-DTPA) is a zwitterion and has a slightly distorted octahedral coordination geometry with one water and one amine in the axial positions, and three carboxylate groups and one amine in the equatorial positions. The complex consists of three five-membered Ga/N/ C/C/O chelate rings and one five-membered Ga/N/C/C/N chelate ring. The Ga-N bonds [Ga1-N1 = 2.081 (4) Å and Ga1-N2 = 2.156 (3)

Supramolecular features
Packing depictions viewed along the a and b axes provided in Figs. 2 and 3, respectively, show pairs of layers containing the complexes parallel to the (001) plane. In the layer, the complexes are linked to each other by O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds (Table 1). Three uncoordinating water

Database survey
In our survey of the Cambridge Structural Database (CSD version 5.39, update November 2017;Groom et al., 2016), we found 64 crystal structures of metal complexes with DTPA. In another search, we found 72 crystal structures of gallium complexes hexa-coordinated by two N and four O atoms.

Synthesis and crystallization
DTPA (50 mg) in acetate buffer (2 mL) adjusted to pH = 4.2 was heated with stirring for dissolution. Gallium nitrate (39.9 mg) was then added to the DTPA solution and the mixture was stirred for at least 10 min at 353 K. The solution was concentrated under ambient pressure at room temperature. When almost all of the solvent had evaporated, methanol was added dropwise to precipitate Ga-DTPA. The precipitate was collected on a 0.22 mm polyamide filter and dried at room temperature. The obtained Ga-DTPA (1.30 mg) was redissolved in ultra-pure water (1 mL) and single crystals suitable for X-ray diffraction were obtained after four weeks by slow diffusion of tetrahydrofuran into the aqueous solution, as illustrated in Fig. 4.

Aqua(2-{[2-({2-[bis(carboxylato-κO-methyl)amino-κN]ethyl}(carboxylato-κO-methyl)amino-κN)ethyl] (carboxymethyl)azaniumyl}acetato)gallium(III) trihydrate
Crystal data  (7) Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.