Preparation of Zirconium-89 Solutions for Radiopharmaceutical Purposes: Interrelation Between Formulation, Radiochemical Purity, Stability and Biodistribution

Abstract

Zirconium-89 is a promising radionuclide for nuclear medicine. The aim of the present work was to find a suitable method for obtaining zirconium-89 solutions for radiopharmaceutical purposes. For this purpose, the ion exchange behavior of zirconium-89 solutions was studied. Radio-TLC (thin layer chromatography) and biodistribution studies were carried out to understand speciation of zirconium-89 complexes and their role in the development of new radiopharmaceuticals. Three methods of zirconium-89 isolation were studied using ZR (hydroxamate) and Chelex-100 resins. It was found that ZR-resin alone is not enough to obtain stable zirconium-89 formulations. An easy and effective method of reconstitution of [⁸⁹Zr]Zr-oxalate to [⁸⁹Zr]Zr-citrate using Chelex-100 resin was developed. Developed procedures allow obtaining [⁸⁹Zr]Zr-oxalate (in 0.1 M sodium oxalate solution) and [⁸⁹Zr]Zr-citrate (in 0.1-1.0 M sodium citrate solution). These solutions are perfectly suitable and convenient for radiopharmaceutical purposes. Our results prove [⁸⁹Zr]Zr-citrate to be advantageous over [⁸⁹Zr]Zr-oxalate. During evaluation of speciation of zirconium-89 complexes, a new TLC method was developed, since it was proved that there is no comprehensive method for analysis or zirconium-89 preparations. The new method provides valuable insights about the content of "active" ionic form of zirconium-89. The interrelation of the chromatographic behavior of zirconium-89 preparations and their biodistribution was studied.

Keywords: Chelex-100; DFO; ZR hydroxamate resin; citrate; oxalate; purification; radiochemical purity; stability; transchelation; zirconium-89.

Figure 1

Dependence of zirconium-89 distribution coefficients (Dg) on oxalic acid concentration for Chelex-100 resin.

Figure 2

Dependence of zirconium-89 elution efficiency using different sodium carboxylates solutions as eluents with Chelex-100 resin (load from 0.5 M oxalic acid medium: losses at the sorption step—0.7%; losses at the washing step (0.1 M oxalic acid)—0.3%).

Figure 3

Dependence of zirconium-89 elution efficiency from Chelex-100 on sodium citrate concentration in eluent.

Figure 4

The dependence of [⁸⁹Zr]Zr-DFO complex formation yield on the amount of chelator for various formulations of zirconium-89.

Figure 5

μPET maximum intensity projections of mice after 24 h p.i. of [⁸⁹Zr]Zr-oxalate samples listed at Table 5: (a) Sample 1; (b) Sample 2; (c) Sample 3; and (d) Sample 4.