Scalable 45ti Cyclotron Production Methods for Radiopharmaceutical Application

Titanium-45 is a positron-emitting radiometal with decay characteristics attractive for clinical positron emission tomography (PET) imaging (t1/2 = 3.08 h, β+ = 84.8%, β+ = .439 MeV). We report methods for producing 45Ti at commercial scale via 13 MeV proton irradiation of spot-welded natSc foil cyclotron targets that are thick to 13 MeV protons and robust to beam currents up to 100 µA, producing tens of GBq (>1 Ci) of 45Ti. Titanium-45 is extracted from bulk natSc via ZR resin and recovered in 0.1 M oxalic acid with radiochemical yields of 72.7 ± 0.6% (n = 3) and 78 ± 3% (n = 3) from 0.25 and 0.5 mm thick natSc targets, respectively. Separation conditions are optimized for rapid and facile radiopharmaceutical incorporation by coordination using siderophore chelators which have previously demonstrated compatibility with 45Ti. Purified 45Ti contains <1 µg natFe and achieves apparent molar activity (AMA) of 29 - 440 GBq/µmol (0.8 – 11.9 Ci/µmol) at EoB for productions ranging from 35 – 122 GBq (0.096 – 3300 Ci). AMAs were determined utilizing the catechol based chelator tren-2,3-dihydroxy-benzamide (TREN-CAM), forming [45Ti][Ti(TREN-CAM)]2-. We observed an increase of AMA in correlation with production size and a decrease of AMA in correlation with increased Sc target mass, indicating that stable contaminants in the target material likely limit currently achievable AMA. The methods described herein establish and validate a robust 45Ti isotope production framework which enables commercial scale production and clinical translation of 45Ti PET agents.