Optimization of ^44gSc Production Using Cyclotron-irradiated Liquid Target

The positron-emitting radionuclide scandium-44 (^44gSc) demonstrates significant potential in tumor diagnosis due to its optimal decay properties (T_1/2=4.04 h, E_\mathrmavg,\textβ^+ =632.0 keV, branching ratio (BR)=94.3%). However, its limited availability has constrained the development of related radiopharmaceuticals. To address this supply limitation, the production of ^44gSc via the reaction ⁴⁴Ca(p,n)^44gSc using a medical cyclotron was reported. Numerical simulations were employed to optimize irradiation parameters for maximizing production yield and radionuclidic purity. Subsequently, proton irradiation of a natural-abundance Ca liquid target was utilized to produce ^44gSc, and the PET imaging performance of ^44gSc was also investigated. To calculate theoretical yield and radionuclidic purity, excitation functions were simulated using TALYS 2.0, ALICE-IPPE, and EMPIRE 3.2 nuclear reaction codes. Based on these calculations, liquid targets containing high-concentration (168 mg/mL) calcium nitrate were irradiated using a GE PETtrace cyclotron. The proton beam was delivered at 14.5 MeV with 7-10 μA intensity for 30-90 min irradiation. After irradiation, the targets were processed through branched DGA resin chromatography for radiochemical purification. Radionuclidic, radiochemical, and chemical purity were assessed using an HPGe detector, TLC scanner, and ICP-OES, respectively. The resulting ^44gScScCl₃ samples (0.33 MBq injection dose) were evaluated through PET imaging studies in murine models to assess their in vivo performance. Numerical simulations demonstrate that 14.5 MeV is the optimal proton energy for the ⁴⁴Ca(p,n)^44gSc reaction, achieving a theoretical radionuclidic purity of 95.8% at the end-of-bombardment (EOB). The primary impurities consist of ⁴³Sc (2.1%), ^44mSc (0.6%), ⁴⁷Sc (0.2%) and ⁴⁸Sc (1.3%). The experimental results show that compared to other tested conditions, the 10 μA beam intensity with 50 min of irradiation delivers a higher yield. The production yield at EOB is 2.5 MBq/μAh for ^44gSc, representing a 3.4-fold improvement over existing data, and the maximum EOB activity is 20.6 MBq. Chemical purification of Sc³⁺ achieves a recovery yield of 97.0%, which is comparable to literature values. The radiochemical purity exceeds 99% as verified by TLC. ICP-OES analysis confirms effective removal of metallic contaminants, retaining only 362.4 ppm Ca while maintaining other metal impurities (Zn, Fe, Al, Mn) below 4 ppm. Radiolabeling studies show that Ca²⁺ exhibits negligible influence on labeling yield. Gamma spectroscopy measurements confirm an EOB radionuclidic purity of 95.8%±1.0%, consistent with simulations. Preliminary PET imaging studies reveal that ^44gSc exhibits high radioactivity levels in the cardiac blood pool, indicating strong binding affinity of free Sc³⁺ to plasma proteins. The PET imaging of ^44gSc achieves high quality even at low doses, supporting its potential for medical diagnostic applications.