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Conjugated Bisphosphonate with High Affinity for Bone As a Bone

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Conjugated Bisphosphonate with High Affinity for Bone As a Bone Development of a Novel 99mTc-Chelate– Conjugated Bisphosphonate with High Affinity for Bone as a Bone Scintigraphic Agent Kazuma Ogawa1,2, Takahiro Mukai1,3, Yasuyuki Inoue1, Masahiro Ono1, and Hideo Saji1 1Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; 2Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan; and 3Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan Key Words: bone scintigraphy; bisphosphonate; 99mTc; MAG3; In bone scintigraphy using 99mTc with methylenediphosphonate HYNIC (99mTc-MDP) and hydroxymethylenediphosphonate (99mTc- J Nucl Med 2006; 47:2042–2047 HMDP), it takes 226 h after an injection before imaging can start. This interval could be shortened with a new radiopharma- ceutical with higher affinity for bone. Here, based on the con- cept of bifunctional radiopharmaceuticals, we designed a Over the last quarter of a century, complexes of 99mTc 99mTc-mercaptoacetylglycylglycylglycine (MAG3)-conjugated with methylenediphosphonate (99mTc-MDP) and hydroxy- 99m hydroxy-bisphosphonate (HBP) ( Tc-MAG3-HBP) and a methylenediphosphonate (99mTc-HMDP) have been widely 99mTc-6-hydrazinopyridine-3-carboxylic acid (HYNIC)-conjugated used as radiopharmaceuticals for bone scintigraphy in cases hydroxy-bisphosphonate (99mTc-HYNIC-HBP). Methods: 99mTc- MAG3-HBP was prepared by complexation of MAG3-HBP with of metastatic bone disease, Paget’s disease, fractures in 99m 99m 99m Tc using SnCl2 as a reductant. The precursor of Tc- osteoporosis, and so forth (1–4). With these Tc-labeled HYNIC-HBP, HYNIC-HBP, was obtained by deprotection of the bisphosphonates, however, an interval of 2–6 h is needed Boc group after the coupling of Boc-HYNIC to a bisphosphonate between injection and bone imaging (3). Shorting this interval derivative. 99mTc-HYNIC-HBP was prepared by a 1-pot reaction would lessen the burden on patients in terms of the total length 99m 2 of HYNIC-HBP with TcO4 , tricine, and 3-acetylpyridine in the of the examination and the dose of radiation absorbed. To presence of SnCl . Affinity for bone was evaluated in vitro by 2 enable imaging at an earlier time after injection, a radiophar- hydroxyapatite-binding assays for 99mTc-HMDP, 99mTc-MAG3- HBP, and 99mTc-HYNIC-HBP. Biodistribution experiments for the maceutical with higher affinity for bone is required. 3 99mTc-labeled compounds were performed on normal rats. Bisphosphonate analogs accumulate in bone because Results: 99mTc-MAG3-HBP and 99mTc-HYNIC-HBP were each their phosphonate groups bind to the Ca21 of hydroxyap- prepared with a radiochemical purity of .95%. In the in vitro bind- atite crystals (5). In the case of 99mTc-MDP and 99mTc- ing assay, 99mTc-MAG3-HBP and 99mTc-HYNIC-HBP had greater HMDP, the phosphonate groups coordinate with technetium 99m affinity for hydroxyapatite than Tc-HMDP. In the biodistribution (6), which might decrease the inherent accumulation of experiments, 99mTc-MAG3-HBP and 99mTc-HYNIC-HBP had MDP and HMDP in bone. Thus, we hypothesized that bone higher levels of radioactivity in bone than 99mTc-HMDP. 99mTc- 99m MAG3-HBP was cleared from the blood slower than 99mTc- affinity of Tc-labeled bisphosphonate would be in- HMDP, whereas there was no significant difference in clearance creased by the design of a bisphosphonate in which the between 99mTc-HYNIC-HBP and 99mTc-HMDP. Consequently, phosphonate groups do not coordinate with technetium, 99mTc-HYNIC-HBP showed a higher bone-to-blood ratio than and we attempted to design a 99mTc-chelate–conjugated 99mTc-HMDP. Conclusion: We developed a novel 99mTc- bisphosphonate based on the concept of bifunctional radio- chelate2conjugated bisphosphonate with high affinity for bone pharmaceuticals (Fig. 1). In this study, mercaptoacetylgly- and rapid clearance from blood, based on the concept of bifunc- cylglycylglycine (MAG3) and 6-hydrazinopyridine-3- tional radiopharmaceuticals. The present findings indicate that 99mTc-HYNIC-HBP holds great potential for bone scintigraphy. carboxylic acid (HYNIC) were chosen as chelating sites because they have been widely used for 99mTc label- ing of proteins and peptides (7–11) and conjugated to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. Then, 99mTc-[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylme- thyl]carbamoylmethyl]carbamoylmethyl]carbamoylme- Received May 9, 2006; Revision accepted Sep. 6, 2006. 99m For correspondence or reprints contact: Hideo Saji, PhD, Department of thanethiolate ( Tc-MAG3-HBP; Fig. 1A) and Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, [99mTc][[4-[(6-hydrazinopyridine-3-carbonyl)amino]-1- Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: [email protected] hydroxy-1-phosphonobutyl]phosphonic acid](tricine)(3- COPYRIGHT ª 2006 by the Society of Nuclear Medicine, Inc. acetylpyridine) (99mTc-HYNIC-HBP; Fig. 1B) were 2042 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 47 • No. 12 • December 2006 FIGURE 1. Chemical structures of 99mTc-MAG3-HBP (A) and 99mTc- HYNIC-HBP (B). prepared by coordination with 99mTc, and their proper- Preparation of 99mTc-HYNIC-HBP ties in vitro and in vivo were compared with these of 2,3,5,6-Tetrafluorophenyl 6-(tert-butoxycarbonyl)-hydrazino- 99mTc-HMDP. pyridine-3-carboxylate (Boc-HYNIC-TFP) and 4-amino-1-hy- droxybutylidene-1,1-bisphosphonate were synthesized according MATERIALS AND METHODS to procedures described preciously (12,13). 4-Amino-1-hydroxy- butylidene-1,1-bisphosphonate (10.3 mg, 41.3 mmol) was sus- Materials pended in 1.33 mL of distilled water, and triethylamine (25.1 mg, 1 Proton nuclear magnetic resonance ( H NMR) spectra were 248 mmol) was added to the suspension. After a few seconds recorded on a Bruker AC-200 spectrometer (JEOL Ltd.), and the of stirring at room temperature, Boc-HYNIC-TFP (17.8 mg, chemical shifts were reported in parts per million downfield from 44.4 mmol) dissolved in 1.33 mL of acetonitrile was added. The an internal 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt reaction mixture was stirred for 3 h at room temperature. RP- standard. Electrospray ionization mass spectra (ESI-MS) were HPLC was performed with a Hydrosphere 5C18 column (20 · 150 obtained with a LCMS-QP8000a (Shimadzu). Thin-layer chro- mm; YMC Co., Ltd) at a flow rate of 16 mL/min with a mixture of matographic analyses were performed with silica plates (Silica gel water, acetonitrile, and formic acid (90:10:1). Chromatograms were 99m 60; Merck KGaA) with acetone as a developing solvent. Tc- obtained by monitoring the ultraviolet (UV) adsorption at a wave- 99m 2 Pertechnetate ( TcO4 ) was eluted in a saline solution on a length of 254 nm. The fraction containing [4-[[6-(tert-butoxycarbonyl)- daily basis from generators (Daiichi Radioisotope Laboratories, hydrazinopyridine-3-carbonyl]amino]-1-hydroxy-1-phosphonobu- 99m Ltd.). Tc-HMDP was prepared by reconstitution with a con- tyl]phosphonic acid (Boc-HYNIC-HBP) was identified by mass ventional HMDP labeling kit (Nihon Medi-Physics Co., Ltd.) with spectrometry and collected. The solvent was removed by lyoph- 99m 2 a TcO4 solution. Other reagents were of reagent grade and ilization to provide Boc-HYNIC-HBP (178 mg, 36.7%) as white were used as received. 1 crystals. H NMR (D2O): d 8.42 (1H, s), 8.33 (1H, d), 7.21 (1H, Preparation of 99mTc-MAG3-HBP d), 3.43 (2H, t), 1.9222.04 (4H, m), 1.47 (9H, s). ESI-MS 2 The precursor of 99mTc-MAG3-HBP, [1-hydroxy-1-phosphono- calculated for C15H26N4O10P2 (M- H) : m/z 483. Found: 483. 4-[2-[2-[2-(2-tritylmercaptoacetylamino)-acetylamino]acetylamino] Boc-HYNIC-HBP (10.4 mg, 21.5 mmol) was stirred in a mixed acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was syn- solution of TFA (720 mL) and anisole (80 mL) for 10 min at room thesized according to procedures described previously (12). The temperature. After removal of the solvent under a stream of trityl group of Tr-MAG3-HBP (0.1 mg) was dissolved in 190 mL N2, the residue was washed with dry ether to produce [4-[(6- of trifluoroacetic acid (TFA) and 10 mL of triethylsilane. After hydrazinopyridine-3-carbonyl)amino]-1-hydroxy-1-phosphonobu- removal of the solvent under a stream of N ,80mL of 0.1 mol/L tyl]phosphonic acid (HYNIC-HBP) quantitatively as white crys- 2 1 borate buffer (pH 9.5) were added to the residue. Next, 3 mLof tals. H NMR (D2O): d 8.33 (1H, s), 8.13 (1H, d), 7.01 (1H, d), SnCl 2H O solution in 0.1 mol/L citrate buffer (pH 5.0) (1 mg/mL) 3.42 (2H, t), 1.9422.04 (4H, m). ESI-MS calculated for 2Á 2 2 99m 2 C10H18N4O8P2 (M- H) : m/z 383. Found: 383. and 200 mLof TcO4 solution were added, and the reaction mixture was vigorously stirred and allowed to react at 95°C for Forty microliters of HYNIC-HBP solution (3.75 mg/mL in 0.1 1h.99mTc-MAG3-HBP was purified by reversed-phase high- mol/L borate buffer, pH 9.5) were mixed successively with performance liquid chromatography (RP-HPLC) performed with a 200 mL of tricine solution (30 mg/mL in 10 mmol/L citrate Cosmosil 5C -AR-300 column (4.6 · 150 mm; Nacalai Tesque) buffer, pH 5.2), 200 mL of 3-acetylpyridine solution (10 mL/mL in 18 99m 2 at a flow rate of 1 mL/min with a mixture of 0.2 mol/L phosphate 10 mmol/L citrate buffer, pH 5.2), 200 mLof TcO4 solution, buffer (pH 6.0) and ethanol (90:10) containing 10 mmol/L tetra- and 25 mL of SnCl2 solution (1.0 mg/mL in 0.1N HCl). The butylammonium hydroxide. reaction mixture was vigorously stirred and allowed to react at 95°C for 35 min. 99mTc-HYNIC-HBP was purified by RP-HPLC Preparation of [[[[(4-Hydroxy-4,4-Diphosphonobutyl) under the same conditions as for the preparation of 99mTc-MAG3- Carbamoylmethyl]Carbamoylmethyl]Carbamoylmethyl] HBP.
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