Serum protein binding displacement: theoretical analysis using a hypothetical radiopharmaceutical and experimental analysis with 123I-N-isopropyl-p-iodoamphetamine

Kawai, Keiichi; Nishii, Ryuichi; Shikano, Naoto; Makino, Nobuo; Kuga, Noriyuki; Yoshimoto, Mitsuyoshi; Jinnouchi, Seishi; Nagamachi, Shigeki; Tamura, Shozo; Takamura, Norito

doi:10.1016/j.nucmedbio.2008.10.005

Cited by 8 publications

(4 citation statements)

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“…The results for the protracted tumor uptake of the [ 64 Cu]Cu-NODAGA-cLAB(1–4)-TATEs herein is in line with brain uptake data for N -isopropyl- p -[ 123 I]iodoamphetamine, a cerebral perfusion radiotracer, which is strongly bound to serum proteins (75%, mainly to albumin and α 1 -acid glycoprotein). Increasing the free fraction of that radiotracer by co-administration of the albumin site II inhibitor 6-methoxy-2-naphthylacetic and/or the α 1 -acid glycoprotein site inhibitor erythromycin accelerated the brain uptake significantly . Furthermore, the shift in the time profile of tumor uptake can also be derived from data for the PSMA ligands 177 Lu-PSMA-ALB-53 and 177 Lu-PSMA-ALB-56 that bear iodine and methyl at the phenylbutanoyl moiety, respectively, and differ 10-fold in their binding affinity to albumin …”

Section: Resultsmentioning

confidence: 99%

“…Increasing the free fraction of that radiotracer by co-administration of the albumin site II inhibitor 6methoxy-2-naphthylacetic and/or the α 1 -acid glycoprotein site inhibitor erythromycin accelerated the brain uptake significantly. 95 Furthermore, the shift in the time profile of tumor uptake can also be derived from data for the PSMA ligands 177 Lu-PSMA-ALB-53 and 177 Lu-PSMA-ALB-56 that bear iodine and methyl at the phenylbutanoyl moiety, respectively, and differ 10-fold in their binding affinity to albumin. 96 In contrast to the tendencies observed for the radioligand kinetics in heart and tumor, all albumin-binding TATEs exhibit a similar shape of the time versus SUV curves for kidneys (Figure 8D As the binding kinetics toward SST 2 in vitro are similar among the TATE derivatives studied herein, other effects might be causative for the enhanced uptake of the albumin binder conjugates in MPC tumors.…”

Section: ■ Introductionmentioning

confidence: 99%

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“Clickable” Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

et al. 2021

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The intentional binding of radioligands to albumin gains increasing attention in the context of radiopharmaceutical cancer therapy as it can lead to an enhanced radioactivity uptake into the tumor lesions and, thus, to a potentially improved therapeutic outcome. However, the influence of the radioligand’s albumin-binding affinity on the time profile of tumor uptake has been only partly addressed so far. Based on the previously identified N ε-4-(4-iodophenyl)butanoyl-lysine scaffold, we designed “clickable” lysine-derived albumin binders (cLABs) and determined their dissociation constants toward albumin by novel assay methods. Structure–activity relationships were derived, and selected cLABs were applied for the modification of the somatostatin receptor subtype 2 ligand (Tyr3)octreotate. These novel conjugates were radiolabeled with copper-64 and subjected to a detailed in vitro and in vivo radiopharmacological characterization. Overall, the results of this study provide an incentive for further investigations of albumin binders for applications in endoradionuclide therapies.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

“Clickable” Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

et al. 2021

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“…If inhibitors with high protein-binding affinity could displace 123 I-IMP serum protein binding, cerebral accumulation of this tracer would be increased. In fact, Kawai et al reported an increase in 123 I-IMP cerebral accumulation in monkeys using the protein-binding displacement method with 6MNA (a major metabolite of nabumetone) (10). We noted that an amino acid infusion could be administered more easily and safely than drugs.…”

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confidence: 64%

“…The radioactivity plateaus in brain were 1.24-and 1.44-fold higher in Proteamin-loading monkeys than those in control monkey 1 and control monkey 2, respectively. Kawai et al reported that the combination of both binding inhibitors (of HSA site II and AGP) appears to exert a synergistic effect in displacement of IMP serum binding (10). It thus appeared that Proteamin treatment increased the free fraction of 123 I-IMP and displaced 123 I-IMP serum binding via a domino effect, yielding rapid and pronounced cerebral accumulation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Competitive Displacement of Serum Protein Binding of Radiopharmaceuticals with Amino Acid Infusion Investigated with N-Isopropyl-p-¹²³I-Iodoamphetamine

Kuga¹,

Shikano²,

Takamura³

et al. 2009

J Nucl Med

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When a therapeutic drug is competitively displaced at the binding sites of serum proteins, the free fraction of the drug will be increased, with an increase in the manifestation of pharmacologic properties. In the case of molecular imaging probes, total clearance and tissue distribution are increased in such circumstances. The aim of this study was to observe the increase in cerebral accumulation of N-isopropyl-p-123 I-iodoamphetamine ( 123 I-IMP) using the protein-binding displacement method with amino acid infusion. Methods: 123 I-IMP binding to human serum was investigated and identified. In addition, protein-binding sites and the specific binding sites of human serum albumin (HSA) and a 1 -acid glycoprotein (AGP) were examined by ultrafiltration. Then, serum-binding sites and the displacement effects of amino acid infusion, including Proteamin 12X Injection and Kidomin, were confirmed in vitro. Subsequently, displacement of 123 I-IMP serum protein binding with Proteamin amino acid infusion was tested in monkeys. A scintigraphic study of 123 I-IMP in monkeys loaded with or without Proteamin was performed, and timeactivity-curves of 123 I-IMP brain accumulation in monkeys were evaluated. Results: 123 I-IMP was bound to HSA site II and AGP to nearly equal extents. Compared with control conditions, loading with Proteamin and Kidomin markedly increased free fractions of binding site markers for HSA site II ( 14 C-diazepam: 0.95% 6 0.04% for control, 1.40% 6 0.06% for Proteamin, 1.62% 6 0.05% for Kidomin) and AGP ( 3 H-propranolol: 10.60% 6 0.32% for control, 13.18% 6 0.14% for Proteamin, 13.82% 6 0.72% for Kidomin). Amino acid infusions were thus suitable for use as displacers for binding site II and AGP. With use of Proteamin amino acid infusion to displace protein binding, the free fraction of 125 I-IMP (14.95% 6 0.74%) was significantly increased in serum (19.24% 6 0.87%). In a 123 I-IMP scintigraphic study of monkeys, average cerebral uptake in 2 monkeys increased by 1.34-fold with Proteamin. Our findings suggested that Proteamin treatment increased the free fraction of 123 I-IMP, yielding rapid and pronounced cerebral accumulation in vivo. Conclusion: Amino acid infusion can improve brain accumulation by competitive displacement of serum protein binding in vivo. Further similar studies are needed with other radiopharmaceuticals.

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Serum albumin: clinical significance of drug binding and development as drug delivery vehicle

Tayyab

Feroz

2021

Advances in Protein Chemistry and Structural Biology

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Serum protein binding displacement: theoretical analysis using a hypothetical radiopharmaceutical and experimental analysis with 123I-N-isopropyl-p-iodoamphetamine

Cited by 8 publications

References 8 publications

“Clickable” Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

“Clickable” Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

Competitive Displacement of Serum Protein Binding of Radiopharmaceuticals with Amino Acid Infusion Investigated with N-Isopropyl-p-¹²³I-Iodoamphetamine

Serum albumin: clinical significance of drug binding and development as drug delivery vehicle

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Serum protein binding displacement: theoretical analysis using a hypothetical radiopharmaceutical and experimental analysis with 123I-N-isopropyl-p-iodoamphetamine

Cited by 8 publications

References 8 publications

“Clickable” Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

“Clickable” Albumin Binders for Modulating the Tumor Uptake of Targeted Radiopharmaceuticals

Competitive Displacement of Serum Protein Binding of Radiopharmaceuticals with Amino Acid Infusion Investigated with N-Isopropyl-p-123I-Iodoamphetamine

Serum albumin: clinical significance of drug binding and development as drug delivery vehicle

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Competitive Displacement of Serum Protein Binding of Radiopharmaceuticals with Amino Acid Infusion Investigated with N-Isopropyl-p-¹²³I-Iodoamphetamine