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Development of a Novel ^99mTc-Chelate–Conjugated Bisphosphonate with High Affinity for Bone as a Bone Scintigraphic Agent

¹ Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; ² Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan; and ³ Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Correspondence: For correspondence or reprints contact: Hideo Saji, PhD, Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: hsaji{at}pharm.kyoto-u.ac.jp

In bone scintigraphy using ^99mTc with methylenediphosphonate (^99mTc-MDP) and hydroxymethylenediphosphonate (^99mTc-HMDP), it takes 2–6 h after an injection before imaging can start. This interval could be shortened with a new radiopharmaceutical with higher affinity for bone. Here, based on the concept of bifunctional radiopharmaceuticals, we designed a ^99mTc-mercaptoacetylglycylglycylglycine (MAG3)-conjugated hydroxy-bisphosphonate (HBP) (^99mTc-MAG3-HBP) and a ^99mTc-6-hydrazinopyridine-3-carboxylic acid (HYNIC)-conjugated hydroxy-bisphosphonate (^99mTc-HYNIC-HBP). Methods: ^99mTc-MAG3-HBP was prepared by complexation of MAG3-HBP with ^99mTc using SnCl₂ as a reductant. The precursor of ^99mTc-HYNIC-HBP, HYNIC-HBP, was obtained by deprotection of the Boc group after the coupling of Boc-HYNIC to a bisphosphonate derivative. ^99mTc-HYNIC-HBP was prepared by a 1-pot reaction of HYNIC-HBP with ^99mTcO₄^–, tricine, and 3-acetylpyridine in the presence of SnCl₂. Affinity for bone was evaluated in vitro by hydroxyapatite-binding assays for ^99mTc-HMDP, ^99mTc-MAG3-HBP, and ^99mTc-HYNIC-HBP. Biodistribution experiments for the 3 ^99mTc-labeled compounds were performed on normal rats. Results: ^99mTc-MAG3-HBP and ^99mTc-HYNIC-HBP were each prepared with a radiochemical purity of >95%. In the in vitro binding assay, ^99mTc-MAG3-HBP and ^99mTc-HYNIC-HBP had greater affinity for hydroxyapatite than ^99mTc-HMDP. In the biodistribution experiments, ^99mTc-MAG3-HBP and ^99mTc-HYNIC-HBP had higher levels of radioactivity in bone than ^99mTc-HMDP. ^99mTc-MAG3-HBP was cleared from the blood slower than ^99mTc-HMDP, whereas there was no significant difference in clearance between ^99mTc-HYNIC-HBP and ^99mTc-HMDP. Consequently, ^99mTc-HYNIC-HBP showed a higher bone-to-blood ratio than ^99mTc-HMDP. Conclusion: We developed a novel ^99mTc-chelate–conjugated bisphosphonate with high affinity for bone and rapid clearance from blood, based on the concept of bifunctional radiopharmaceuticals. The present findings indicate that ^99mTc-HYNIC-HBP holds great potential for bone scintigraphy.

Key Words: bone scintigraphy • bisphosphonate • ^99mTc • MAG3 • HYNIC

COPYRIGHT © 2006 by the Society of Nuclear Medicine, Inc.

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