A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
27560354
DOI
10.1016/j.nucmedbio.2016.07.009
PII: S0969-8051(16)30135-4
Knihovny.cz E-resources
- Keywords
- (68)Ga, Albumin-binder, Bisphosphonate, Bone metastases, DOTA, PET,
- MeSH
- Adsorption MeSH
- Diphosphonates chemistry metabolism pharmacokinetics MeSH
- Heterocyclic Compounds, 1-Ring chemistry MeSH
- Durapatite chemistry MeSH
- Bone and Bones diagnostic imaging metabolism MeSH
- Rats MeSH
- Humans MeSH
- Rats, Wistar MeSH
- Positron-Emission Tomography MeSH
- Gallium Radioisotopes MeSH
- Serum Albumin metabolism MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid MeSH Browser
- Diphosphonates MeSH
- Heterocyclic Compounds, 1-Ring MeSH
- Durapatite MeSH
- Gallium Radioisotopes MeSH
- Serum Albumin MeSH
Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)MBP (L1). The ligands were labeled with 68Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [68Ga]L1. [68Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [68Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [68Ga]L1 than for [68Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in 177Lu therapeutic agent with the same ligand (a theranostic pair).
Department of Inorganic Chemistry Charles University Prague Czech Republic
Department of Nuclear Medicine University Hospital Mainz Germany
Institute of Nuclear Chemistry Johannes Gutenberg University Mainz Germany
References provided by Crossref.org
