An osteoclast-targeting agent for imaging and therapy of bone metastasis

Abstract

A hybrid compound (DO3A-BP) featuring a radiometal bifunctional chelator (1,4,7,N',N", DOTA) and an osteoclast-targeting moiety (bisphosphonate) was designed and synthesized. The 111 In-labeled complex of DO3A-BP showed significantly elevated uptake in osteoclasts compared to the undifferentiated adherent bone marrow derived cells. Biodistribution studies revealed a favorable tissue distribution profile in normal mice with high bone uptake and long retention, and low or negligible accumulation in non-target organs. KeywordsBone metastasis; imaging agent; osteoclast; Indium-111; bifunctional chelator; bisphosphonate A variety of cancers preferentially metastasize to the skeleton at their advanced stages. Wholebody scan using 99m Tc-MDP (MDP: methylene diphosphonate) is currently the standard clinic practice for the detection of bone metastases. 1, 2 However, due to its low specificity a final diagnosis is often aided by other imaging modalities, such as X-ray radiography, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography, and/ or bone marrow biopsy. 3, 4 Of the clinical methods to treat bone metastases, therapies utilizing bisphosphonates (BPs) and radiopharmaceuticals play critical roles. To date, several BPs have been approved by the FDA 5 and they are commonly used to treat skeletal complications caused by metastases and other bone diseases, including tumor-associated osteolysis, 6, 7 hypercalcemia, 8 Paget's disease, 9, 10 and osteoporosis. 11 As shown in Figure 1, bisphosphonates are a group of compounds with a chemical structure similar to that of the natural inorganic pyrophosphate (PPi), an endogenous regulator of bone mineralization, but differing in the central atom where BPs have a methylene carbon rather than an oxygen atom in PPi. This structural feature renders BPs resistant to hydrolysis under acidic conditions or by pyrophosphatases. Varieties of BPs could be obtained by tuning the R 2 side chain while leaving the R 1 group intact as either -OH or -H. 12 It has recently become clear that BPs first bind avidly to the bone mineral surface and are subsequently internalized selectively by osteoclasts, where they inhibit the osteoclastic activity and induce apoptosis. In addition, BPs have been *Corresponding author. Tel.: +1 214 645 5978; fax: +1 214 645 5885; email: Xiankai.Sun@UTSouthwestern.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. found to inhibit tumor cell adhesion to mineralized bone as well as tumor cell invasion and proliferation. 13, 14 NIH Public AccessAuthor Manuscript Bioorg Med Chem Lett. ...

Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

“…Thus, compounds containing a bis(phosphonate) moiety are efficiently adsorbed on surface of bones. The applications include imaging techniques ( 111 In and 68 Ga for Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging, respectively) (13,15,(17)(18)(19) as well as therapy ( 177 Lu, 90 Y) (13,16) or bone metastases pain palliation in human patients (20). Recently, we and others have developed bis(phosphonate)-bearing ligands based on a DOTAlike macrocyclic core (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, Fig.…”

“…1) as carriers for metal ions to be delivered to calcified tissue (12)(13)(14)(15)(16)(17). The applications include imaging techniques ( 111 In and 68 Ga for Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging, respectively) (13,15,(17)(18)(19) as well as therapy ( 177 Lu, 90 Y) (13,16) or bone metastases pain palliation in human patients (20). The conjugates exhibited a very high affinity to HAP as bis(phosphonate) moiety is not coordinated to central metal ion and, thus, remains active for bone targeting (21,22).…”

Targeting the αvβ3 Integrin for Small-Animal PET/CT of Osteolytic Bone Metastases

“…Current work has been directed toward the development of imaging and therapeutic agents such as bisphosphonates that directly target osteoclasts or substances that disrupt bone resorption mechanisms by inhibiting the action of biomolecules such as receptor activator for nuclear factor κ B ligand and cathepsin K (7–12). The α v β 3 integrin is another biomolecule that can be exploited to target osteoclasts through imaging and therapy.…”

Preparation and biodistribution assessment of 111In-BPAMD as a novel agent for bone SPECT imaging

“…The long length of examination can offend the patients and more importantly than that, the slow clearance can result in the great absorbed dose to the soft tissues. Besides, 99m Tc-MDP has shown low specificity and therefore the ultimate diagnosis is often followed by other imaging modalities [magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and bone marrow biopsy] [22].…”