Tc-Labeled mercaptoacetylglycylglycylglycine conjugated to hydroxy-bisphosphonate

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 exhibit a very high affinity for hydroxyapatite (HA), a component of the bone matrix (1). The NBPs tend to accumulate in osteoclasts at areas of increased bone metabolism by inhibiting the farnesyl diphosphate synthase, an important enzyme of the mevalonate pathway in the cell (2). Several BPs and NBPs are available commercially 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 bone metastases. However, these compounds have limitations primarily because they either exist as a mixture of anionic compounds with varying properties (e.g., [Tc]-labeled methylene-diphosphonate (MDP) or [Tc]-labeled hydroxymethylene-diphosphonate (HMDP)) or are rapidly degraded (e.g., [Re]MDP) under conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue (3). The Tc- or Re-labeled BPs were suggested to have these limitations because the compounds possess dual activities: one phosphonate group of the BP molecule acts as a radionuclide chelator, and the other phosphonate group binds to the target(s). Therefore, due to close proximity of the two groups, one activity may be interfering with the other (3). To circumvent problems associated with the radiolabeled BPs, investigators developed NBPs with two independent activities such that the nitrogen-containing part would only chelate the radiotracer and the BP part would target the bone (4). Ogawa et al. synthesized and labeled two NBPs, mercaptoacetylglycylglycylglycine-hydroxy-bisphosphonate (MAG3-HBP) and 6-hydrazinopyridine-3-carboxylic acid-hydroxy-bisphosphonate (HYNIC-HBP), with Tc to obtain [Tc]MAG3-HBP and [Tc]HYNIC-HBP (4). The two imaging agents were valuated for binding to hydroxyapatite (HA) under conditions and for biodistribution in normal rats (4). This chapter presents the studies performed and the results obtained with [Tc]MAG3-HBP. The studies and the results obtained with [Tc]HYNIC-HBP are presented in a separate chapter in MICAD (www.micad.nih.gov) (5).