| [PMID]: | 28898054 |
| [Au] Autor: | Müller C; Farkas R; Borgna F; Schmid RM; Benesová M; Schibli R |
| [Ad] Endereço: | Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut , 5232 Villigen-PSI, Switzerland. |
| [Ti] Título: | Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals. |
| [So] Source: | Bioconjug Chem;28(9):2372-2383, 2017 Sep 20. |
| [Is] ISSN: | 1520-4812 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | The development of (radio)pharmaceuticals with favorable pharmacokinetic profiles is crucial for allowing the optimization of the imaging or therapeutic potential and the minimization of undesired side effects. The aim of this study was, therefore, to evaluate and compare three different plasma protein binders (PPB-01, PPB-02, and PPB-03) that are potentially useful in combination with (radio)pharmaceuticals to enhance their half-life in the blood. The entities were functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator via a l-lysine and ß-alanine linker moiety using solid-phase peptide chemistry and labeled with Lu (T = 6.65 days), a clinically established radiometal. The binding capacities of these radioligands and Lu-DOTA were evaluated using human plasma and solutions of human serum albumin (HSA), human α -acid glycoprotein (α -AGP), and human transthyretin (hTTR) by applying an ultrafiltration assay. Lu-DOTA-PPB-01 and Lu-DOTA-PPB-02 bound to a high and moderate extent to human plasma proteins (>90% and ∼70%, respectively), whereas the binding to hTTR was considered negligible (<10%). Lu-DOTA-PPB-03 showed almost complete binding to human plasma proteins (>90%) with a high fraction bound to hTTR (∼50%). Plasma protein binding of the Lu-DOTA complex, which was used as a control, was not observed (<1%). Lu-DOTA-PPB-01 and Lu-DOTA-PPB-02 were both displaced (>80%) from HSA by ibuprofen, specific for Sudlow's binding site II and coherent with the aromatic structures, and >80% by their respective binding entities. Lu-DOTA-PPB-03 was displaced from hTTR by the site-marker l-thyroxine (>60%) and by its binding entity PPB-03* (>80%). All three radioligands were investigated with regard to the in vivo blood clearance in normal mice. Lu-DOTA-PPB-01 showed the slowest blood clearance (T : >15 h) followed by Lu-DOTA-PPB-03 (T : ∼2.33 h) and Lu-DOTA-PPB-02 (T : ∼1.14 h), which was excreted relatively fast. Our results confirmed the high affinity of the 4-(4-iodophenyl)-butyric acid entity (PPB-01) to plasma proteins, while replacement of the halogen by an ethynyl entity (PPB-02) reduced the plasma protein binding significantly. An attractive approach is the application of the transthyretin binder (PPB-03), which shows high affinity to hTTR. Future studies in our laboratory will be focused on the application of these binding entities in combination with clinically relevant targeting agents for diagnostic and therapeutic purposes in nuclear medicine. |
| [Mh] Termos MeSH primário: |
Proteínas Sanguíneas/metabolismo
Lutécio/metabolismo
Compostos Radiofarmacêuticos/metabolismo
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| [Mh] Termos MeSH secundário: |
Animais
Feminino
Seres Humanos
Ligantes
Lutécio/química
Lutécio/farmacocinética
Camundongos Endogâmicos BALB C
Pré-Albumina/metabolismo
Ligação Proteica
Radioisótopos/química
Radioisótopos/metabolismo
Radioisótopos/farmacocinética
Compostos Radiofarmacêuticos/química
Compostos Radiofarmacêuticos/farmacocinética
Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos
Tiroxina/metabolismo
Distribuição Tecidual
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Blood Proteins); 0 (Ligands); 0 (Prealbumin); 0 (Radioisotopes); 0 (Radiopharmaceuticals); 5H0DOZ21UJ (Lutetium); Q51BO43MG4 (Thyroxine) |
| [Em] Mês de entrada: | 1710 |
| [Cu] Atualização por classe: | 171009 |
[Lr] Data última revisão:
| 171009 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170913 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1021/acs.bioconjchem.7b00378 |
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