Production and quality control 177Lu (NCA)-DOTMP as a potential agent for bone pain palliation

Abstract

Skeletal uptake of radiolabeled-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetramethylene phosphoric acid (e.g., 177Lu-DOTMP) complex, is used for bone pain palliation. The moderate energy of β-emitting 177Lu (T½ = 6.7 d, Eβmax = 497keV) has been considered as a potential radionuclide for development of the bone-seeking radiopharmaceutical. Since the specific activity of the radiolabeled carrier molecules should be high, the "no-carrier-added radionuclides" have sig-nificant roles in nuclear medicine. Many researchers illustrated no-carrier-added 177Lu production; among these separation techniques such as ion exchange chromatography, reversed phase ion-pair, and electrochemical method, extraction chromatography has been considered more capable than other methods. In order to optimize the conditions, some effective factors on separation of Lu/Yb were investigated by EXC. The NCA 177Lu, produced by this method, was mixed with 300 μl of DOTMP solution (20 mg in 1 mL of 0.5 M NaHCO3, pH = 8) and incu-bated under stirring at room temperature for 45 min. Radiochemical purity of the 177Lu-DOTMP complex was determined using radio-thin-layer chromatography (RTLC) method. The complex was injected to wild-type rats and biodistribution was then studied for seven days. The NCA 177Lu was produced with specific activ-ity of 48 Ci/mg and with a radinuclidic purity of 99.99% through irradiation of enriched 176Yb target (1 mg) in a thermal neutron flux of 4 × 1013 n.cm-2.s-1 for 14 days. 177Lu-DOTMP was obtained with high radiochemical purities (> 98%) under optimized reaction conditions. The radiolabeled complex exhibited excellent stability at room temperature. Biodistribution of the radiolabeled complex studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation within the other nontargeted organs.

Figure 1

The gamma ray spectra of (a) the irradiated ¹⁷⁶Yb (NO₃)₃ target and (b) the final product after the separation.

Figure 2

The flowsheet of EXC separation.

Figure 3

The resulting profile for the elution of ¹⁷⁷Lu.

Figure 4

The effect of the initial mass of ytterbium (a) 5 mg, (b) 10 mg, and (c) 20 mg (bed volume = 5 mL, bed height = 20 cm, column diameter = 1.1 cm, flow rate of loading = 2 mL/min, and flow rate of eluting = 5 mL/min).

Figure 5

The effect of temperature on separation of Yb and Lu on column 1 (a) 30°C and (b) 50°C (Bed volume = 5 mL, bed height = 20 cm, column diameter = 1.1 cm, flow rate of loading = 2 mL/min, and flow rate of eluting = 5 mL/min).

Figure 6

RTLC chromatographs for (a) the free NCA ¹⁷⁷Lu and (b) the NCA ¹⁷⁷Lu‐DOTMP in normal saline as eluent on Whatman paper.

Figure 7

%ID/g of NCA ¹⁷⁷Lu‐DOTMP in wild‐type rat tissues at 4 hrs, 24 hrs, 48 hrs, and 7 days postinjection.