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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. (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 alpha(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 time-activity-curves of (123)I-IMP brain accumulation in monkeys were evaluated. (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% +/- 0.04% for control, 1.40% +/- 0.06% for Proteamin, 1.62% +/- 0.05% for Kidomin) and AGP ((3)H-propranolol: 10.60% +/- 0.32% for control, 13.18% +/- 0.14% for Proteamin, 13.82% +/- 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% +/- 0.74%) was significantly increased in serum (19.24% +/- 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. Amino acid infusion can improve brain accumulation by competitive displacement of serum protein binding in vivo. Further similar studies are needed with other radiopharmaceuticals.


Noriyuki Kuga, Naoto Shikano, Norito Takamura, Ryuichi Nishii, Keishi Yamasaki, Masato Kobayashi, Shigeki Nagamachi, Shozo Tamura, Keiichi Kawai. Competitive displacement of serum protein binding of radiopharmaceuticals with amino acid infusion investigated with N-isopropyl-p-123I-iodoamphetamine. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2009 Aug;50(8):1378-83

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PMID: 19617322

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