A new bone imaging agent, ⁹⁹Tc^m-BIPrDP, its preparation and biological properties

Objective: To investigate the feasibility of ⁹⁹Tc^m-1-hydroxy-3-(2-butyl-1H-imidazol-1-yl) propane-1, 1-diphosphonic acid (BIPrDP) as a new bone imaging agent. Methods: BIPrDP was synthesized by three steps from the raw material 2-butyl-1H-imidazole. ⁹⁹Tc^m-BIPrDP were prepared with mixed BIPrDP (50 mg/ml, 100 μl) and freshly eluted Na⁹⁹Tc^mO₄ (37.0 MBq) in the presence of the reducing agent SnCl₂ (1 rng/ml, 100 μl) at boiling temperature for 30 min. The labeling yield and stability of ⁹⁹Tc^m-BIPrDP were measured with TLC. Partition coefficient in octanol-water and plasma protein binding ratio to human heparin anticoagulation plasma of ⁹⁹Tc^m-BIPrDP was checked. ICR mice were sacrificed at 5, 10, 15, 30, 60, 120 and 240 min after tail vein injection of 0.2 ml (7.4 MBq) freshly prepared ⁹⁹Tc^m-BIPrDP.Samples of blood, heart, liver, spleen, lung, kidney, bone, muscle, gonad, intestine, stomach and brain were taken, weighed and the gamma counts measured. The biodistribution of the radiolabeled compound in different organs was calculated and expressed as % ID/g. Bone-to-organ uptake ratios were calculated by the % ID/g values. The kinetics of blood clearance was calculated. Bone imaging was performed in New Zealand rabbit after intravenous injection of ⁹⁹Tc^m-BIPrDP. One-way analysis of variance was used to analyze the % ID/g at different times points. Results: Radiolabeling yield of ⁹⁹Tc^m-BIPrDP was more than 95% and the labeled complex was stable at least up to 6 h in vitro. The octanol-water partition coefficients (log P) for ⁹⁹Tc^m-BIPrDP were-2.396 ± 0.035 and-2.242 ± 0.025 at pH values of 7.0 and 7.4, respectively. The plasma protein binding rate of ⁹⁹Tc^m-BIPrDP was (47.07 ± 0.05)%. The bone uptake of ⁹⁹Tc^m-BIPrDP in mice reached a maximum of 19.20 % ID/g at 30 min after injection, and this high level of uptake persisted 4 h later at 18.98 % ID/g. Kidney uptake was highest among all the non-target organs,but decreased from 24.50 % ID/g at 5 min to 5.22 % ID/g at 4 h. The labeling compounds were excreted mainly through the kidneys, and the uptake in other important organs were extremely low. The muscle and brain exhibited the two lowest uptake, with values of 0.18 % ID/g and 0.03 % ID/g at 4 h, respectively. The uptake of blood was 18.60 % ID/g at 5 min,and then decreased rapidly; the uptake was only 0.40 % ID/g at 4 h.The pharmacokinetic equation was C=9.109e^-0.262t + 2.696e^-0.00558t. From the blood kinetic curve, it was concluded that the complex ⁹⁹Tc^m-BIPrDP eliminated rapidly from the blood, which was consistent with the biodistribution results in mice. A clear bone image of rabbit was obtained 1 h after the injection of ⁹⁹Tc^m-BIPrDP, which suggested that the selectivity of bone absorption was very good. Low uptake and rapid clearance in other soft tissues could be seen from the whole-body images. The % ID/g at different time points was significantly different (F=5.65-859.24, all P<0.05). Conclusion: The preparation of ⁹⁹Tc^m-BIPrDP is convenient and exhibits high uptake in bone,which suggests its potential as a novel bone imaging agent. (authors)