Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation.
To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (186Re) that contains a hydroxyl group at the central carbon of its bisphosphonate structure, we attached a stable 186Re-MAMA chelate to the amino group of a 4-amino butylidene-bisphosphonate derivative [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-HBP) and we investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on affinity for hydroxyapatite and on biodistribution by conducting a comparative study with [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-BP). The precursor of 186Re-MAMA-HBP, trityl (Tr)-MAMA-HBP, was obtained by coupling a Tr-MAMA derivative to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. 186Re-MAMA-HBP was prepared by a reaction with 186ReO(4-) and SnCl2 in citrate buffer after the deprotection of the Tr groups of Tr-MAMA-HBP. After reversed-phase high-performance liquid chromatography, 186Re-MAMA-HBP had a radiochemical purity of over 95%. Compared with 186Re-MAMA-BP, 186Re-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into 186Re complex-conjugated bisphosphonates would be effective in enhancing accumulation in bones. These findings provide useful information on the design of bone-seeking therapeutic radiopharmaceuticals.
Ogawa
Kazuma
K
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Mukai
Takahiro
T
Arano
Yasushi
Y
Otaka
Akira
A
Ueda
Masashi
M
Uehara
Tomoya
T
Magata
Yasuhiro
Y
Hashimoto
Kazuyuki
K
Saji
Hideo
H
D000818:Animals; D004164:Diphosphonates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017886:Durapatite / Q000378:metabolism*; D005266:Femoral Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D010166:Palliative Care / Q000379:methods; D011877:Radionuclide Imaging; D014018:Tissue Distribution
C512981:(N-(2-((3-(3,3-diphosphonopropylcarbamoyl)propyl)-2-thioethylamino)acetyl)-2-aminoethanethiolate)oxorhenium(V); C512982:(N-(2-((4-((4-hydroxy-4,4-diphosphonobutyl)amino)-4-oxobutyl)-2-thioethylamino)acetyl)-2-aminoethanethiolate)oxorhenium(V); D004164:Diphosphonates; D009942:Organometallic Compounds; D017886:Durapatite