Chelators for 68Ga radiopharmaceuticals

Sudhakara Reddy Seelam,정재민,이윤상 대한방사성의약품학회 2016 Journal of radiopharmaceuticals and molecular prob Vol.2 No.1

68Ga is a promising radionuclide for positron emission tomography (PET). It is a generator-produced (68Ge/68Ga-generator) radionuclide with a half-life of 68 min. The employment of 68Ga for basic research and clinical applications is growing exponentially. Bifunctional chelators (BFCs) that can be efficiently radiolabeled with 68Ga to yield complexes with good in vivo stability are needed. Given the practical advantages of 68Ga in PET applications, gallium complexes are gaining increasing attention in biomedical imaging. However, new 68Ga-labeled radiopharmaceuticals that can replace 18F-labeled agents like [18F]fluorodeoxyglucose (FDG) are needed. The majority of 68Ga-labeled derivatives currently in use consist of peptide agents, but the development of other agents, such as amino acid or nitroimidazole derivatives and glycosylated human serum albumin, is being actively pursued in many laboratories. Thus, the availability of new 68Ga-labeled radiopharmaceuticals with high impact is expected in the near future. Here, we present an overview of the different new classes of chelators for application in molecular imaging using 68Ga PET. J Radiopharm Mol Prob 2(1):22-36, 2016

Comparative study of 2-nitroimidazole-fluorophore-conjugated derivatives with pimonidazole for imaging tumor hypoxia

Sudhakara Reddy Seelam,Jae Min Jeong,Mi Kyung Hong a,Yun-Sang Lee 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.2

Herein, 2-nitroimidazole-fluorophore conjugates were synthesized by linking 2-nitroimidazole and FITCor RITC via thiourea bonds. The prepared derivatives were stable for 2 h in Dulbecco’s modified Eagle’smedium (DMEM) at 37 °C. The novel conjugates were studied for their in vitro uptake under hypoxic conditionsusing U87MG and CT-26 cell lines, showing significantly higher uptakes in hypoxic than normoxic cells. Immunohistochemical analysis confirmed hypoxia in U87MG and CT-26 xenografted tumor tissues. Moreover,the prepared conjugates were evaluated by in vivo experiments after intravenous injection in U87MG andCT-26 xenografted mice. Hypoxia was confirmed by immunohistochemistry of the prepared derivatives withco-injected pimonidazole. Confocal microscopy of the prepared derivatives showed strong fluorescence inhypoxic tumor tissues correlated with the pimonidazole distribution. This suggested that the 2-nitroimidazolefluorophoreconjugates are promising optical imaging probes for tumor hypoxia and are promising substitutesfor pimonidazole immunohistochemistry, which requires a multi-step procedure of incubation involving antibody,second antibody, dye, hydrogen peroxide, and multiple washing steps.

[18F]Labeled 2-nitroimidazole derivatives for hypoxia imaging

Sudhakara Reddy Seelam,정재민,이윤상 대한방사성의약품학회 2016 Journal of radiopharmaceuticals and molecular prob Vol.2 No.2

Imaging hypoxia using positron emission tomography (PET) is of great importance for cancer therapy. [18F] Fluoromisonidazole (FMISO) was the first PET agent used for imaging tumor hypoxia. Various radiolabeled nitroimidazole derivatives such as [18F]fluoroerythronitroimidazole (FETNIM), [18F]1-α-D-(2-deoxy-2-fluoroarabinofuranosyl)-2nitroimidazole(FAZA), 2-(2-nitroimidazol-1-yl)-N-(3,3,3-[18F]-trifluoropropyl)acetamide ([18F]EF-3), [18F]2-(2-nitro-1Himidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), 3-[18F]fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)1H-1,2,3,-triazol-1-yl)-propan-1-ol ([18F]HX-4), and [18F]fluoroetanidazole (FETA) were developed successively. However, these imaging agents still produce PET images with limited resolution; the lower blood flow in hypoxic tumors compared to normoxic tumors results in low uptake of the agents in hypoxic tumors. Thus, the development of better imaging agents is necessary. J Radiopharm Mol Probes 2(2):73-83, 2016

188Re Labeled liver therapeutic drugs for hepatic carcinoma (HCC)

Sudhakara Reddy Seelam,Yun Sang Lee,Vinay Kumar Banka,Jae Min Jeong 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1

188Re is one of the most readily available generator derived and useful radionuclides for therapy emitting βˉparticles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%). The 188W/188Regenerator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (NCA) 188Resuitable for the preparation of radiopharmaceuticals for radionuclide therapy. Rhenium-188 has been used forthe preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis,rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticalsbased on 188Re -labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. In this review, we addressed the current development status of 188Re radiopharmaceuticals for liver cancertherapy and their applications.

Biodistribution and PET imaging of [18F]FMISO in mousecolon cancer xenografted mice

Sudhakara Reddy Seelam,이지윤,김영주,이윤상,정재민 대한방사성의약품학회 2015 Journal of radiopharmaceuticals and molecular prob Vol.1 No.2

Hypoxia is an important adverse prognostic factor for tumor progression and is a major cause of failure of radiation therapy. In case of short-term hypoxia, the metabolism can recover to normal, but if hypoxia persists, it causes irreversible cell damage and finally leads to death. So a hypoxia marker would be very useful in oncology. In particular, 2-nitroimidazole can be reduced to form a reactive chemical species, which can bind irreversibly to cell components in the absence of sufficient oxygen, thus, the development of radiolabeled nitroimidazole derivatives for the imaging of hypoxia remains an active field of research to improve cancer therapy result. 2-nitroimidazole based hypoxia marker, [18F]FMISO holds promise for the evaluation of tumor hypoxia by Positron emission tomography (PET), at both global and local levels. In the present study, [18F]FMISO was synthesized using an automatic synthesis module with high radiochemical purity (>99%) in 60 min. Immunohistochemical analysis using pimonidazole confirmed the presence of hypoxia in xenografted CT-26 tumor tissue. A biodistribution study in CT-26 xenografted mice showed that the increased tumor-to-muscle ratio and tumor-to-blood ratios from 10 to 120 min post-injection. In the PET study, [18F]FMISO also showed increased tumor-to-muscle ratios from 10 to 120 min post-injection. In conclusion, this study demonstrates the feasibility and utility of [18F]FMISO for imaging hypoxia in mouse colon cancer model using small animal PET. J Radiopharm Mol Probes 1(2):137-144, 2015

Comparative study of 2-nitroimidazole-fluorophore-conjugated derivatives with pimonidazole for imaging tumor hypoxia

Seelam, Sudhakara Reddy,Hong, Mi Kyung,Lee, Yun-Sang,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.2

Herein, 2-nitroimidazole-fluorophore conjugates were synthesized by linking 2-nitroimidazole and FITC or RITC via thiourea bonds. The prepared derivatives were stable for 2 h in Dulbecco's modified Eagle's medium (DMEM) at 37 ℃. The novel conjugates were studied for their in vitro uptake under hypoxic conditions using U87MG and CT-26 cell lines, showing significantly higher uptakes in hypoxic than normoxic cells. Immunohistochemical analysis confirmed hypoxia in U87MG and CT-26 xenografted tumor tissues. Moreover, the prepared conjugates were evaluated by in vivo experiments after intravenous injection in U87MG and CT-26 xenografted mice. Hypoxia was confirmed by immunohistochemistry of the prepared derivatives with co-injected pimonidazole. Confocal microscopy of the prepared derivatives showed strong fluorescence in hypoxic tumor tissues correlated with the pimonidazole distribution. This suggested that the 2-nitroimidazole-fluorophore conjugates are promising optical imaging probes for tumor hypoxia and are promising substitutes for pimonidazole immunohistochemistry, which requires a multi-step procedure of incubation involving antibody, second antibody, dye, hydrogen peroxide, and multiple washing steps.

[¹⁸F]Labeled 2-nitroimidazole derivatives for hypoxia imaging

Seelam, Sudhakara Reddy,Lee, Yun-Sang,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2016 Journal of radiopharmaceuticals and molecular prob Vol.2 No.2

Imaging hypoxia using positron emission tomography (PET) is of great importance for cancer therapy. [$^{18}F$] Fluoromisonidazole (FMISO) was the first PET agent used for imaging tumor hypoxia. Various radiolabeled nitroimidazole derivatives such as [$^{18}F$]fluoroerythronitroimidazole (FETNIM), [$^{18}F$]1-${\alpha}$-D-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole(FAZA), 2-(2-nitroimidazol-1-yl)-N-(3,3,3-[18F]-trifluoropropyl)acetamide ([$^{18}F$]EF-3), [$^{18}F$]2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), 3-[$^{18}F$]fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3,-triazol-1-yl)-propan-1-ol ([$^{18}F$]HX-4), and [$^{18}F$]fluoroetanidazole (FETA) were developed successively. However, these imaging agents still produce PET images with limited resolution; the lower blood flow in hypoxic tumors compared to normoxic tumors results in low uptake of the agents in hypoxic tumors. Thus, the development of better imaging agents is necessary.

Chelators for ⁶⁸Ga radiopharmaceuticals

Seelam, Sudhakara Reddy,Lee, Yun-Sang,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2016 Journal of radiopharmaceuticals and molecular prob Vol.2 No.1

$^{68}Ga$ is a promising radionuclide for positron emission tomography (PET). It is a generator-produced ($^{68}Ge/^{68}Ga$-generator) radionuclide with a half-life of 68 min. The employment of $^{68}Ga$ for basic research and clinical applications is growing exponentially. Bifunctional chelators (BFCs) that can be efficiently radiolabeled with $^{68}Ga$ to yield complexes with good in vivo stability are needed. Given the practical advantages of $^{68}Ga$ in PET applications, gallium complexes are gaining increasing attention in biomedical imaging. However, new $^{68}Ga$-labeled radiopharmaceuticals that can replace $^{18}F$-labeled agents like [$^{18}F$]fluorodeoxyglucose (FDG) are needed. The majority of $^{68}Ga$-labeled derivatives currently in use consist of peptide agents, but the development of other agents, such as amino acid or nitroimidazole derivatives and glycosylated human serum albumin, is being actively pursued in many laboratories. Thus, the availability of new $^{68}Ga$-labeled radiopharmaceuticals with high impact is expected in the near future. Here, we present an overview of the different new classes of chelators for application in molecular imaging using $^{68}Ga$ PET.

Biodistribution and PET imaging of [¹⁸F]FMISO in mousecolon cancer xenografted mice

Seelam, Sudhakara Reddy,Lee, Ji Youn,Kim, Young Joo,Lee, Yun-Sang,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2015 Journal of radiopharmaceuticals and molecular prob Vol.1 No.2

Hypoxia is an important adverse prognostic factor for tumor progression and is a major cause of failure of radiation therapy. In case of short-term hypoxia, the metabolism can recover to normal, but if hypoxia persists, it causes irreversible cell damage and finally leads to death. So a hypoxia marker would be very useful in oncology. In particular, 2-nitroimidazole can be reduced to form a reactive chemical species, which can bind irreversibly to cell components in the absence of sufficient oxygen, thus, the development of radiolabeled nitroimidazole derivatives for the imaging of hypoxia remains an active field of research to improve cancer therapy result. 2-nitroimidazole based hypoxia marker, [$^{18}F$]FMISO holds promise for the evaluation of tumor hypoxia by Positron emission tomography (PET), at both global and local levels. In the present study, [$^{18}F$]FMISO was synthesized using an automatic synthesis module with high radiochemical purity (>99%) in 60 min. Immunohistochemical analysis using pimonidazole confirmed the presence of hypoxia in xenografted CT-26 tumor tissue. A biodistribution study in CT-26 xenografted mice showed that the increased tumor-to-muscle ratio and tumor-to-blood ratios from 10 to 120 min post-injection. In the PET study, [$^{18}F$]FMISO also showed increased tumor-to-muscle ratios from 10 to 120 min post-injection. In conclusion, this study demonstrates the feasibility and utility of [$^{18}F$]FMISO for imaging hypoxiain mouse colon cancer model using small animal PET.

¹⁸⁸Re Labeled liver therapeutic drugs for hepatic carcinoma (HCC)

Seelam, Sudhakara Reddy,Banka, Vinay Kumar,Lee, Yun-Sang,Jeong, Jae Min Korean Society of Radiopharmaceuticals and Molecul 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.1

$^{188}Re$ is one of the most readily available generator derived and useful radionuclides for therapy emitting ${\beta}^-$ particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%). The $^{188}W/^{188}Re$ generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (NCA) $^{188}Re$ suitable for the preparation of radiopharmaceuticals for radionuclide therapy. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on $^{188}Re$ -labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. In this review, we addressed the current development status of $^{188}Re$ radiopharmaceuticals for liver cancer therapy and their applications.