Research articleRhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation
Introduction
Many cancers, especially breast and prostate carcinomas, have a strong propensity to metastasize to the bone [1]. Bone metastases are usually associated with severe pain, which has an important impact on quality of life [2]. Standard treatment options for bone metastases include external beam radiotherapy [3], while internal radiotherapy with radiopharmaceuticals would be preferable if the patient has a large number of metastatic lesions [4], [5].
Rhenium-186 (186Re) is a useful radionuclide for internal radiotherapy. Thus, rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain [6], [7], [8], [9]. However, 186Re-HEDP showed delayed blood clearance and high gastric uptake of radioactivity upon injection [10]. These features were attributed to the generation of 186ReO4− resulting from the instability of this 186Re complex in vivo [11], [12]. To improve the instability of 186Re-HEDP based on the concept of bifunctional radiopharmaceuticals, we recently developed a new 186Re-labeled bisphosphonate derivative through the conjugation of a stable 186Re complex to a bisphosphonate analog [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-BP); Fig. 1A]. As expected, 186Re-MAMA-BP was considerably more stable than 186Re-HEDP in vitro [13].
Previous studies of bisphosphonates suggest that a hydroxyl group at a central carbon of the bisphosphonate structure affects the affinity for bone minerals [14], [15]. Since extensive accumulation in bones is a definitive requirement for a therapeutic drug in the palliation of metastatic bone pain, we designed a 186Re-MAMA-BP derivative with a hydroxyl group at a central carbon of the bisphosphonate structure, [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (6) (186Re-MAMA-HBP; Fig. 1B) in order to develop a 186Re-labeled compound with greater accumulation in the bone. In this study, we synthesized 186Re-MAMA-HBP and evaluated the effect of introducing a hydroxyl group at a central carbon of the bisphosphonate structure on the affinity for hydroxyapatite and on in vivo accumulation in the bone by studying and comparing it with 186Re-HEDP and 186Re-MAMA-BP.
Section snippets
Materials
Ion spray mass spectrum was obtained with an APIIIIE triple quadrupole mass spectrometer (Perkin-Elmer Science Instruments, Thornhill, Canada). Thin-layer chromatography (TLC) analyses were performed with silica plates (Silica Gel 60; Merck KGaA, Darmstadt, Germany), with acetone as developing solvent. 186Re was supplied as 186ReO4− by the Japan Atomic Energy Research Institute (Ibaraki, Japan) [16]. 186Re-MAMA-BP and 186Re-HEDP were synthesized as described previously [13]. Other reagents were
Preparation of 186Re-MAMA-HBP
For the synthesis of the precursor of 186Re-MAMA-BP, Tr-MAMA-BP, a bisphosphoric tetraethyl ester derivative was conjugated with compound (1) (Tr-MAMA derivative) in the presence of DCC. After the hydrolysis of tetraethyl esters, Tr-MAMA-BP was obtained in good yield [13]. However, for the synthesis of the 186Re-MAMA-HBP precursor, Tr-MAMA-HBP, bisphosphoric tetraalkyl esters with a hydroxyl group at the central carbon could not be synthesized. Thus, a bisphosphonate derivative (3) that has no
Discussion
The basic requirements for the effective use of radiopharmaceuticals in internal radiotherapy for the palliation of metastatic bone pain include extensive accumulation in the bone following peripheral administration.
Bisphosphonates have been used widely as inhibitors of bone resorption for the treatment of bone diseases and have been investigated extensively [21], [22]. All bisphosphonates contain two phosphonate groups attached to a single carbon atom, forming a P–C–P structure; this central
Acknowledgments
This work was supported, in part, by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a research grant from the Sagawa Foundation for the Promotion of Cancer Research.
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