Abstract
1894
Objectives: False-negative bone scintigraphies have been reported in patients with previous bisphosphonate (BP) treatment. Our recent study showed that pre-treatment of HEDP caused a delay in blood clearance of both polynuclear 186Re-HEDP and a mononuclear 186Re-chelate- conjugated BP in mice, due to a competition for renal BP transporter(s). This suggests that bone-seeking radiopharmaceuticals that possess bone-binding site other than BP group may be advantageous to circumvent the problem. Since oligo-aspartic acid (oligo-Asp) possesses a high affinity for bone, 99mTc-L,L-1,2- ethylenedicysteine (EC) complexes with one or two (D-Asp)5 group were designed, synthesized and evaluated.
Methods: One or two (D-Asp)5 groups were conjugated to EC to prepare EC-(D-Asp)5 or EC-[(D-Asp)5]2, respectively. A (D-Asp)10 group was also conjugated to EC to prepare EC-(D-Asp)10. After 99mTc labeling with 99mTc-gluco- hepatonate, plasma stability, plasma protein binding, hydroxyapatite (HA) binding and biodistribution in mice were compared. The effect of HEDP pre-administration on the biodistribution was also investigated.
Results: Three 99mTc-lableled oligo-Asp showed HPLC retention times identical to those of well characterized non-radioactive respective Re complexes. All the 99mTc complexes remained stable in plasma and exhibited low plasma protein binding. The HA binding of 99mTc-EC-[(D-Asp)5]2 was similar and significantly higher to 99mTc-EC-(D- Asp)10 and than 99mTc-EC-(Asp)5. When injected to mice, 99mTc-EC-[(D-Asp)5]2 showed similar and significantly higher bone accumulation to 99mTc-EC(D-Asp)10 and than 99mTc-EC(D-Asp)5. 99mTc-EC-[(D-Asp)5]2 exhibited the fastest clearance of radioactivity from blood among the three. As a result, 99mTc-EC-[(D-Asp)5]2 provided the highest bone-to-blood ratios of 258 and 638 at 1 and 3 h postinjection. No significant differences were observed in blood clearance and renal radioactivity levels when 99mTc-EC-[(D-Asp)5]2 was injected in mice after 5 min injection of HEDP.
Conclusions: 99mTc-EC-[(D-Asp)5]2 provided the most preferable pharmacokinetics for bone imaging, which was not affected by HEDP pre-treatment. Although further optimization of oligo-Asp length was required, the findings in this study suggest that 99mTc-EC-[(D-Asp)5]2 would constitute a lead compound for developing new class of bone seeking radiopharmaceuticals.
- Society of Nuclear Medicine, Inc.