The continuous liquid–liquid extraction of the PET radioisotope 45Ti using a membrane-based separator allows for efficient 45Ti recovery and radiolabeling.

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

A switch from batch to continuous manufacturing of gallium-68 (68 Ga) and 68 Ga-labeled pharmaceuticals can be advantageous, as it recycles isotopically-enriched zinc-68 (68 Zn), removes pre-and post-irradiation target manipulations, and provides scalability via dose-on-demand production. Herein we report efficient extraction of radiogallium (66,67,68 Ga = *Ga) from ZnCl 2 /HCl solutions in batch and in flow using a membrane-based liquidliquid separator. From 5.6 M ZnCl 2 /3 M HCl, a 1/2 (v/v) diisopropyl ether (i Pr 2 O)/trifluorotoluene (TFT) solvent extracts 76.3 ± 1.9% of *Ga and 1.9 ± 1.6% of Zn in flow using a single pass through. From 1 M ZnCl 2 /6 M HCl, a 1/2 (v/v) n-butyl methyl ether (n-BuOMe)/TFT solvent extracts 95.7 ± 2.0% of *Ga and 0.005 ± 0.003% of Zn in flow. TFT plays a key role in controlling the interfacial tension between the aqueous and the organic phases, ensuring clean membrane-based separation. The process did not extract Cu, Mn, and Co but did extract Fe. Using HGaCl 4 and ZnCl 2 as the extractable species, the COSMO-RS theory predicts the solvation-driven extraction of Ga and Zn with a mean unsigned error of prediction of 4.0% and 3.4% respectively. KEYWORDS Gallium-68; gallium-67; liquid-liquid extraction in flow; COSMO-RS 68 Ge/ 68 Ga-generators further contribute to 68 Ga popularity in clinical and pre-clinical settings. [6] Meeting the growing demand for 68 Ga is a challenge, as it is mostly supplied by the gallium generators which suffer from high prices, long lead time, quality inconsistencies, and limited shelf life. [7] An alternative method of 68 Ga production is the irradiation of 68 Zn using a cyclotron. [8] Since many PET-centers have their own cyclotrons, this is potentially a convenient means of in-house production of 68 Ga-tracers. However, the cyclotron production of 68 Ga in solid targets from 68 Zn

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