• Journal of Radiopharmaceuticals and Molecular Probes
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• v.7 no.2
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• pp.85-91
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• 2021

Selective amino acid conjugation of bulky antibodies is a valuable asset for real-time diagnosis and therapy. However, selective conjugation incorporating a chelate-bearing radioactive atom into an antibody without affecting its immunoreactivity is a challenging task. A bifunctional chelator (BFC), a selective amino acid-targeting probe, and a linker have been developed to overcome this problem. Here, we report the synthesis of a novel propylene cross-bridged chelator (PCB)-1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane (TE2A)-luminol BFC via a click reaction and radiolabel it with a ⁶⁴Cu ion for tyrosine-selective conjugation of trastuzumab. In the initial optimization study, we tried different oxidative addition conditions such as electro-oxidation, hemin, horseradish peroxidase, iodogen tube, chloramine-T, and iodo beads. In this study, up to 82% of ⁶⁴Cu-PCB-TE2A-luminol was conjugated with the antibody in an iodo bead-catalyzed oxidative addition reaction with an isolated yield of 24.4%.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.8 no.1
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• pp.45-49
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• 2022

With the development of monoclonal antibodies, therapeutic or diagnostic radioisotope has been successfully delivered at tumor sites with high selectivity for antigens. Different approaches have been applied to improve the tumor-to-normal ratio by considering the in vivo stability of radioimmunoconjugates as a prerequisite. Various stable and inert antibody radiolabeling techniques for radioimmunoconjugate preparation have been extensively evaluated to enhance in vivo stability. Antibody radiolabeling techniques should be rapid and easy; they should not disrupt the immunoreactivity and in vivo behavior of antibodies, which are coupled with a bifunctional chelator (BFC) to stably coordinate with a radiometal. For the design of BFCs, radiometal coordination properties must be considered. However, various diagnostic radionuclides, such as ⁸⁹Zr, ⁶⁴Cu, ⁶⁸Ga, ¹¹¹ln, and ^99mTc, or therapeutic radionuclides, such as ¹⁷⁷Lu, ⁶⁷Cu, ⁹⁰Y, and ²²⁵Ac, have been increasingly used for antibody radiolabeling. In addition to useful radionuclides, ⁶⁴Cu and ¹⁷⁷Lu with the most accessible or the highest production rates in many countries should be considered. In this review, we mainly discussed antibody radiolabeling techniques and conditions that involve ⁶⁴Cu and ¹⁷⁷Lu radiometals.

• Archives of Pharmacal Research
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• v.27 no.9
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• pp.961-967
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• 2004

The development of an antibody labeling method with $^{99m}$Tc is important for cancer imaging. Most bifunctional chelate methods for $^{99m}$Tc labeling of antibody incorporate a $^{99m}$Tc chelator through a linkage to lysine residue. In the present study, a novel site-specific $^{99m}$Tc labeling method at carbohydrate side chain in the Fc region of 2 antibodies (T101 and rabbit anti-human serum albumin antibody (RPAb)) using dihydrazinophthalazine (DHZ) which has 2 hydrazino groups was developed. The antibodies were oxidized with sodium periodate to pro-duce aldehyde on the Fc region. Then, one hydrazine group of DHZ was conjugated with an aldehyde group of antibody through the formation of a hydrazone. The other hydrazine group was used for labeling with $^{99m}$Tc. The number of conjugated DHZ was 1.7 per antibody. $^{99m}$Tc labeling efficiency was 46-85％ for T101 and 67∼87％ for RPAb. Indirect labeling with DHZ conjugated antibodies showed higher stability than direct labeling with reduced antibodies. High immunoreactivities were conserved for both indirectly and directly labeled antibodies. A biodistribution study found high blood activity related to directly labeled T1 01 at early time point as well as low liver activity due to indirectly labeled T101 at later time point. However, these findings do not affect practical use. No significantly different biodistribution was observed in the other organs. The research concluded that DHZ can be used as a site-specific bifunctional chelating agent for labeling antibody with $^{99m}$Tc. Moreover, $^{99m}$Tc labeled antibody via DHZ was found to have excellent chemical and biological properties for nuclear medicine imaging.edicine imaging.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.3 no.2
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• pp.103-112
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• 2017

The combination of nanoparticle with radioisotope could give the in vivo information with high sensitivity and specificity. However, radioisotope labeling of nanoparticle is very difficult and radioisotopes have different physicochemical properties, so the radioisotope selection of nanoparticle should be carefully considered. $^{18}F$ was first option to be considered for labeling of nanoparticle. For the labeling of $^{18}F$ with nanoparticle, Prosthetic group is widely used. Iodine, another radioactive halogen, is often used. Since radioiodine isotopes are various, they can be used for different imaging technique or therapy in the same labeling procedures. $^{99m}Tc$ can easily be obtained as pertechnatate ($^{99m}{TcO_4}^-$) by commercial generator. Ionic $^{68}Ga$ (III) in dilute HCl solution is also obtained by generator system, but $^{68}Ga$ can be substituted for $^{67}Ga$ because of the short half-life (67.8 min). $^{64}Cu$ emits not only positron but also ${\beta}-particle$. Therefore $^{64}Cu$ can be used for imaging and therapy at the same time. These radioactive metals can be labeled with nanoparticle using the bifunctional chelator. $^{89}Zr$ has longer half-life (78.4 h) and is used for the longer imaging time. Unlike different metals, $^{89}Zr$ should use the other chelate such as DFO, 3,4,3-(LI-1,2-HOPO) or DFOB.

• Journal of Radiation Industry
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• v.9 no.4
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• pp.193-198
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• 2015

Most of targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells to produce its cytotoxic effect. Either small molecule drugs or monoclonal antibodies are mostly used in targeted therapies. Unfortunately, targeted therapy has a certain degree of unwanted side effect like other cytotoxicity inducing chemotherapies. To overcome and to reduce unwanted side effects during a cancer therapy, recently radiopeptide therapies has got the worlds' attraction for the tumor targeting modalities due to its beneficial effect on less side effect compared to cytotoxic chemotherapies. Among radiopeptide therapies, $^{177}Lu$-DOTATATE is a major modality as an effective one invented so far in treating neuroendocrine tumor (NET) and it has been in clinical trials at least one decade. Although it does have rather effective therapeutic effect on NET, it has less effective in rather large solid tumor. There are many ways to improve or increase therapeutic effect of radiopeptide are a finding the potent small molecules to target the tumor site selectively, or a labeling with radioisotope of emitting high energy, or an improving its biological half-life by introducing different moieties to increase lipophilicity. Present study was focus to increase a biological half-life of radio somatostatin which will target the somatostatin receptor by altering the bifunctional chelator (BFCA) by introducing lipophilic moiety to the somatostatin, which would make the labeled peptide stay longer in the tumor site and thus it can intensify the therapeutic effect on tumor cell itself and around tissues.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.2 no.2
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• pp.108-112
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• 2016

Molecular imaging with the radiolabeled RGD peptides for ${\alpha}_v{\beta}_3$ integrin has been an increasing interest for tumor diagnosis and the treatment monitoring. Recently, $^{64}Cu$-NODAGA-gluco-E[c(RGDfK)]$_2$ was developed for quantification of ${\alpha}_v{\beta}_3$ integrin and its biological properties was elucidated. To better understand the molecular process in vivo, we performed the kinetic analysis for the $^{64}Cu$-NODAGA-gluco-E[c(RGDfK)]$_2$. After preparation of a radiotracer, dynamic PET images were obtained in the U87MG xenograft mice for 60 min (n = 6). Binding potential values were estimated from the 3-tissue compartment model, reference Logan and simplified reference tissue model. In the early time frame (0-20 min), the liver, kidney, intestine, urinary bladder and tumor were visualized but these uptakes were diminished as time went by. The tumors showed a good contrast at 40 min after administration. $^{64}Cu$-NODAGA-gluco-E[c(RGDfK)]$_2$ showed the 2-fold uptake in the tumor compared with that in the muscle. The parametric maps for binding values also provide the higher tumor-to-background contrast than the static images. A binding value obtained from the 3-tissue compartment model was comparable to other modeling methods. From these results, we conclude that $^{64}Cu$-NODAGA-gluco-E[c(RGDfK)]$_2$ may be a promising PET radiotracer for the evaluation of angiogenesis.