Re-Labeled [-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V)

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBPs) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds have a very high affinity for hydroxyapatite (HA), a component of the bone matrix. These phosphonates or their derivatives tend to accumulate in osteoclasts located at areas of increased bone metabolism by inhibiting the enzyme farnesyl diphosphate (or pyrophosphate) synthase, an important enzyme of the cellular mevalonate pathway, which is involved in protein prenylation (1). The mechanism of action of BPs and the NBPs has been described in detail by Drake et. al. (2). Several BPs and NBPs are commercially available for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with Tc or Re and used for the imaging and treatment of pain as a result of bone metastases from cancer such as that of the breast or the prostate (3). However, these compounds have limited efficacy primarily because they exist either as a mixture of anionic compounds with varying properties (e.g., Tc-labeled methyl diphosphonate (MDP)) or are unstable (e.g., Re-labeled 1-hydroxyethylidene-1,1-diphosphonate) under conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue such as the gastric lining of the stomach (4). The limited clinical utility of radiolabeled BPs was suggested to be caused by the dual activities exhibited by the compounds: one phosphonate group acts as a radionuclide chelator, and the other phosphonate group binds to the target(s). Therefore, due to the close proximity of the two groups, one activity may be interfering with the other (4). In an effort to solve the stability problems observed with the Re-labeled NBPs, Ogawa et al. developed two new NBPs, Re-[-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethylenethiolate] oxorhenium (V) ([Re]MAMA-BP) and its hydroxylated derivative, Re-[-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) ([Re]MAMA-HBP) (3). The two compounds were then compared for their affinity to HA under conditions and the biodistribution of the radiochemicals was investigated in normal mice. This chapter presents the results obtained with [Re]MAMA-HBP. Results obtained with [Re]MAMA-BP are presented in a separate chapter of MICAD (5).