Radiopharmaceutical Precursors for Theranostics

Due to the complex nomenclature used in various regulations and guidance documents, the understanding of radiopharmaceutical precursor’s definition might be challenging. Depending on the context it could be interpreted as the substance which becomes a radiopharmaceutical after radiolabeling with a radionuclide of choice or a radionuclide which is used for radiolabeling of that substance. In this Chapter we present and discuss the requirements for precursors which are used in the preparation of theranostic radiopharmaceuticals, in particular for preparation of new radiopharmaceuticals for clinical trials within the EU. In discussion on the available methods for assessing the quality of radiopharmaceutical precursors and on the specified limits the reference to Ph. Eur. is made. Since the EANM guidelines for in-house preparation of radiopharmaceuticals also specify the need for testing the quality of radiopharmaceutical precursors, information provided herein might help the radiopharmacist working on the development of new theranostic agents to adequately define identity, strength, quality, purity and stability of the final radiopharmaceutical preparation

New synthesis route of active substance d,l-HMPAO for preparation Technetium Tc99m Exametazime

BACKGROUND: Technetium Tc99m Exametazime (99mTc-HMPAO) is currently used as a radiopharmaceutical for determining regional cerebral blood flow and for the labelling of autologous leucocytes for infection and inflammation imaging. The HMPAO ligand exists in two diastereomeric forms: d,l and meso. Usually, the substance is obtained in low chemical yield in a time consuming procedure. Furthermore, the final product still contains some amounts of the meso-form. The aim of this study was to develop the efficient, reliable and fast method for isolation of the d,l-HMPAO, which would provide the ligand with high purity and free from the meso-diastereomer. MATERIAL AND METHODS: The mixture of the meso- and d,l-HMPAO was synthesized in two-steps by condensation of propanediamine with keto-oxime and the reduction of the obtained bisimine. The d- and l-enantiomers were separated individually directly from this mixture by repeated crystallizations from ethanol as their tartrate salts and pooled together in equal proportions. That substance was characterized for its identity and isomeric purity using IR, HPLC and GC methods. The meso-free d,l-HMPAO was used for the preparation of the radiopharmaceutical freeze-dried kit for technetium-99m radiolabelling. Quality assessment of obtained 99mTc-d,l-HMPAO complex was performed according to the current Ph.Eur. monograph 1925 and USP monograph — Technetium Tc99m Exametazime Injection. To verify its biological activity, the kit-prepared 99mTc-d,l-HMPAO has been used for the white blood cell (WBC) labelling. RESULTS: According to the proposed synthesis route the d,l-HMPAO was obtained with around 18–20% yield in the total time of 10 days. The ligand identity was confirmed and the HPLC analysis revealed more than 99% chemical purity. The undesired meso-form was not detected. Freeze dried kit formulation for 99mTc-labelling of d,l-HMPAO has been established and four batches of kits were manufactured. The radiochemical purity of 99mTc-d,l-HMPAO complex was high (> 95% of lipophilic technetium-99m exametazime). Brain uptake in rats reached 2.1 ± 0.3%. The in vitro labelling of WBC resulted in 68.3 ± 6.6% yield. CONCLUSION: A new synthesis method of d,l-HMPAO, drug substance for technetium-99m exametazime preparation has been developed