Over the past decade, the scientific community involved in the research and development of therapeutic radiopharmaceuticals (RPhs), has been taking growing interest in the isotope of the rare-earth element, Lu. 177Lu radionuclide (T1/2 = 6.65 days) exerts the properties of a “soft” β—emitter (Eβmax = 498 keV), which makes it convenient for treatment of small malignant formations (the maximum range in soft tissues Lmax = 2 mm) of different nature and localization, and the gamma component (Eγ = 208 keV) allows to visualize the agent biodistribution by means of scintigraphic imaging.
Lutetium is the smallest representative of lanthanides with a characteristic degree of oxidation (+3) and abilities to form complexes with various ligands, in particular with electron-donor bifunctional chelating agents (DTPA, DOTA, EDTA) conjugated to a molecule specific to receptors on the surface of a malignant cell, this principle underlies the Peptide Receptor Radionuclide Therapy (PRRT). Thus, selecting the optimal peptide transporter, it becomes possible to control the biodistribution of 177Lu in a patient's body, and the use of a chelator with a high stability constant of the metal complex (lg KML) results in minimizing the diffusion of free 177Lu ions into healthy organs and tissues.
177LuCl3 salt in a 0.05 M solution of HCl is used as an active pharmaceutical substance when producing RPh for PRRT. However, the possibility of using different target materials to obtain 177Lu in the reactor according to the following reactions:
176Yb (n,γ) 177Yb 177Lu + β- + ῡe (1)
176Lu (n,γ) 177Lu + 177mLu (2)
leads to formation of two types of raw material: without a carrier (NCA) and with a carrier (CA), distinguished by the amount of lutetium isotopic impurities, which decrease the specific activity of the finished RPh. Meanwhile the presence of the long-lived nuclear isomer, 177mLu, (T1/2 = 160 days) in the raw material leads to an increase in unreasonable radiation loads on the patient's body.
The works on labeling of the peptide, the octreotide analogue with a conjugated chelator: DOTA-Tyr3-octreotate (DOTA-TATE) by means of 177LuCl3 NCA raw material (SA = 102.41 Ci/mg at the moment of first labeling) and CA (SA = 30.2 Ci/mg at the moment of first labeling) were carried out. In both cases, the peptide sample weight, the reaction mixture volume and the synthesis conditions remained unchanged, but 177LuCl3 volumetric and specific activity was changed.
The aim of the work done was to identify the optimal molar ratio of peptide to lutetium (νpept : νLu), and of peptide to lutetium-177 isotope (νpept : ν177Lu) for both types of raw material. The effect of a decrease in the specific activity of the raw material during storage on the yield of the labeling reaction was considered. The control indicator of the finished product quality was the incorporation yield of 177Lu+3 ions into the composition of the transporter molecule of not less than 95 %, defined by ITLC and HPTLC methods in the system ammonium acetate - methanol.