Gwang Il An

Korea Institute of Radiological & Medical Sciences, Sŏul, Seoul, South Korea

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Publications (28)76.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastrin‑releasing peptide receptor (GRPR) is overexpressed by a variety of human tumors and in particular, identified to be upregulated in prostate cancers. The current study aimed to develop clinically translatable BBN analogue‑based radioligands for positron emission tomography (PET) of GRPR‑positive tumors. We developed radiolabeled BBN analogues and modified radiolabeled galacto‑BBN analogues and then investigated their tumor‑targeting efficacy in vivo. The chelator 1,4,7‑triazacyclononane, 1‑glutaric acid‑4,7 acetic acid (NODAGA) was used to radiolabel the peptides with 64Cu. The peptides were evaluated by measuring cell‑based receptor‑binding affinities. Biodistribution experiments and small animal imaging using PET were performed in nude mice bearing subcutaneous PC3 human prostate cancer xenografts. The conjugates were radiolabeled with yields >99%. The stability assay showed that [64Cu]NODAGA‑BBN and [64Cu]NODAGA‑galacto‑BBN remained stable in both human and mouse serum for 1 h at 37˚C. PET images of PC3 tumor‑bearing nude mice were acquired at 1, 3, 24, 48 and 72 h after injection. [64Cu]NODAGA‑galacto‑BBN showed retention in tumors for 72 h, low liver uptake, and rapid renal clearance. PET imaging results were also confirmed by biodistrubution 1 and 3 h after injection. [64Cu]NODAGA‑BBN and [64Cu]NODAGA‑galacto‑BBN are promising new PET probes for GRPR‑positive prostate cancer.
    International journal of oncology. 01/2015;
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    ABSTRACT: Apoptosis has a role in many medical disorders and treatments; hence, its non-invasive evaluation is one of the most riveting research topics. Currently annexin V is used as gold standard for imaging apoptosis. However, several drawbacks, including high background, slow body clearance, make it a suboptimum marker for apoptosis imaging. In this study, we radiolabeled the recently identified histone H1 targeting peptide (ApoPep-1) and evaluated its potential as a new apoptosis imaging agent in various animal models. ApoPep-1 (CQRPPR) was synthesized, and an extra tyrosine residue was added to its N-terminal end for radiolabeling. This peptide was radiolabeled with (124)I and (131)I and was tested for its serum stability. Surgery- and drug-induced apoptotic rat models were prepared for apoptosis evaluation, and PET imaging was performed. Doxorubicin was used for xenograft tumor treatment in mice, and the induced apoptosis was studied. Tumor metabolism and proliferation were assessed by [(18)F]FDG and [(18)F]FLT PET imaging and compared with ApoPep-1 after doxorubicin treatment. The peptide was radiolabeled at high purity, and it showed reasonably good stability in serum. Cell death was easily imaged by radiolabeled ApoPep-1 in an ischemia surgery model. And, liver apoptosis was more clearly identified by ApoPep-1 rather than [(124)I]annexin V in cycloheximide-treated models. Three doxorubicin doses inhibited tumor growth, which was evaluated by 30-40 % decreases of [(18)F]FDG and [(18)F]FLT PET uptake in the tumor area. However, ApoPep-1 demonstrated more than 200 % increase in tumor uptake after chemotherapy, while annexin V did not show any meaningful uptake in the tumor compared with the background. Biodistribution data were also in good agreement with the microPET imaging results. All of the experimental data clearly demonstrated high potential of the radiolabeled ApoPep-1 for in vivo apoptosis imaging.
    APOPTOSIS 01/2015; 20(1):110-21. · 3.61 Impact Factor
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    ABSTRACT: This study aims to monitor how the change of cell survival of transplanted adipose-derived stem cells (ADSCs) responds to myocardial infarction (MI) via the hexadecyl-4-(124)I-iodobenzoate ((124)I-HIB) mediated direct labeling method in vivo. Stem cells have shown the potential to improve cardiac function after MI. However, monitoring of the fate of transplanted stem cells at target sites is still unclear. Rat ADSCs were labeled with (124)I-HIB, and radiolabeled ADSCs were transplanted into the myocardium of normal and MI model. In the group of (124)I-HIB-labeled ADSC transplantation, in vivo imaging was performed using small-animal positron emission tomography (PET)/computed tomography (CT) for 9days. Twenty-one days post-transplantation, histopathological analysis and apoptosis assay were performed. ADSC viability and differentiation were not affected by (124)I-HIB labeling. In vivo tracking of the (124)I-HIB-labeled ADSCs was possible for 9 and 3days in normal and MI model, respectively. Apoptosis of transplanted cells increased in the MI model compared than that in normal myocardium. We developed a direct labeling agent, (124)I-HIB, and first tried to longitudinally monitor transplanted stem cell to MI. This approach may provide new insights on the roles of stem cell monitoring in living bodies for stem cell therapy from pre-clinical studies to clinical trials. Copyright © 2014 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 11/2014; · 2.28 Impact Factor
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    ABSTRACT: Two new bicyclic arginine-glycine-aspartic acid (RGD) peptides, c(RGD-ACP-K) (1a) and c(RGD-ACH-K) (1b), incorporating the aminocyclopentane (ACP) and aminocyclohexane (ACH) carboxylic acids, respectively, were synthesized by grafting the aminocycloalkane carboxylic acids onto the tetra-peptide RGDK sequence. These peptides and their conjugates with DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid) (2a-b) exhibit high affinity toward U87MG glioblastoma cells. Their affinity is greater than that exhibited by c(RGDyK). Labeling these conjugates with radiometal (64)Cu resulted in high radiochemical yields (>97%) of the corresponding complexes, abbreviated as c(RGD-ACP-K)-DOTA-(64)Cu (3a) and c(RGD-ACH-K)-DOTA-(64)Cu (3b). Both 3a and 3b are stable for 24 h in human and mouse serums and show high tumor uptake, as observed by positron emission tomography (PET). Blocking experiments with 3a and 3b by preinjection of c(RGDyK) confirmed their target specificity and demonstrated their promise as PET radiotracers for imaging ανβ3-positive tumors.
    ACS Medicinal Chemistry Letters 09/2014; 5(9):979-82. · 3.07 Impact Factor
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    ABSTRACT: The first macrocyclic bifunctional chelator incorporating propylene cross-bridges was efficiently synthesized from cyclam in seven steps. After the introduction of an extra functional group for facile conjugation onto the propylene cross-bridge, the two carboxylic acid pendants could contribute to strong coordination of Cu(II) ions, leading to an robust Cu-complex. The cyclic RGD peptide conjugate of PCB-TE2A-NCS was prepared and successfully radiolabeled with 64Cu ion. The radiolabeled peptide conjugate was evaluated in vivo through a biodistribution study and animal PET imaging to demonstrate high tumor uptake with low background.
    Journal of Medicinal Chemistry 08/2014; 57(17):7234-7243. · 5.48 Impact Factor
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    ABSTRACT: Copper is an essential cofactor for a variety of biochemical processes including oxidative phosphorylation, cellular antioxidant activity, and elimination of free radicals. The copper transporter 1 is known to be involved in cellular uptake of copper ions. In this study, we evaluated the utility of human copper transporter 1 (hCTR1) gene as a new reporter gene for (64)Cu PET imaging.
    Journal of Nuclear Medicine 08/2014; 55(10). · 5.56 Impact Factor
  • Nuclear Medicine and Biology 08/2014; 41(7):629-630. · 2.41 Impact Factor
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    ABSTRACT: By developing a new bi-modal radioactive tracer that emits both luminescence and nuclear signals, a trimodal liposome for optical, nuclear, and MR imaging is efficiently prepared. Fast clearance of the radiotracer from reticuloendothelial systems enables vivid tumor imaging with minimum background.
    ACS Medicinal Chemistry Letters 02/2014; · 3.07 Impact Factor
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    ABSTRACT: N-mono/dimethylated TE2A tetraazamacrocycles (MM-TE2A and DM-TE2A) were synthesized in high yields. Both Cu-MM/DM-TE2A complexes showed increased kinetic stability compared to that of Cu-TE2A, whereas Cu-DM-TE2A showed even higher in vitro stability than that of Cu-ECB-TE2A. MM-TE2A and DM-TE2A were quantitatively radiolabeled with 64Cu ions and showed rapid clearance from the body to emerge as a potential efficient bifunctional chelator.
    ACS Medicinal Chemistry Letters 07/2013; · 3.07 Impact Factor
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    ABSTRACT: A new tetraazamacrocyclic bifunctional chelator, TE2A-Bn-NCS was synthesized in high overall yield from cyclam. An extra functional group (NCS) was introduced to N-atom of TE2A for specific conjugation with antibody. The Cu complex of TE2A-Bn-NCS showed high kinetic stability in acidic decomplexation and cyclic voltammetry studies. X-ray structure determination of Cu-TE2A-Bn-NH2 complex confirmed octahedral geometry, in which copper atom is strongly coordinated by four macrocyclic nitrogens in equatorial positions and two carboxylate oxygen atoms occupy the elongated axial positions. Trastuzumab was conjugated with TE2A-Bn-NCS and then radiolabeled with 64Cu quantitatively at room temperature within 10 min. Biodistribution studies showed that the 64Cu-labeled TE2A-Bn-NCS-trastuzumab conjugates maintain high stability in physiological conditions, and NIH3T6.7 tumors were clearly visualized up to 3 days by 64Cu-immuno-positron emission tomgraphy imaging in animal models.
    Bioconjugate Chemistry 07/2013; · 4.82 Impact Factor
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    ABSTRACT: Although the prognosis of patients with differentiated thyroid carcinoma (DTC) is generally encouraging, a diagnostic dilemma is posed when an increasing level of serum thyroglobulin (Tg) is noted, without detection of a recurrent tumor using conventional imaging tools such as the iodine-131 whole-body scanning (the [(131)I] scan) or neck ultrasonography (US). The objective of the present study was to evaluate the diagnostic value of [(124)I]-PET/CT and [(18)F]-FDG-PET/CT in terms of accurate detection of both iodine- and non-iodine-avid recurrence, compared with that of conventional imaging such as the [(131)I] scan or neck ultrasonography (US). Between July 2009 and June 2010, we prospectively studied 19 DTC patients with elevated thyroglobulin levels but who do not show pathological lesions when conventional imaging modalities are used. All involved patients had undergone total thyroidectomy and radioiodine (RI) treatment, and who had been followed-up for a mean of 13 months (range, 6-21 months) after the last RI session. Combined [(18)F]-FDG-PET/CT and [(124)I]-PET/CT data were evaluated for detecting recurrent DTC lesions in study patients and compared with those of other radiological and/or cytological investigations. Nine of 19 patients (47.4%) showed pathological [(18)F]-FDG (5/19, 26.3%) or [(124)I]-PET (4/19, 21.1%) uptake, and were classed as true-positives. Among such patients, disease management was modified in six (66.7%) and disease was restaged in seven (77.8%). In particular, the use of the described imaging combination optimized planning of surgical resection to deal with locoregional recurrence in 21.1% (4/19) of patients, who were shown to be disease-free during follow-up after surgery. Our results indicate that combination of [(18)F]-FDG-PET/CT and [(124)I]-PET/CT affords a valuable diagnostic method that can be used to make therapeutic decisions in patients with DTC who are tumor-free on conventional imaging studies but who have high Tg levels.
    Journal of Korean medical science 09/2012; 27(9):1019-26. · 0.84 Impact Factor
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    ABSTRACT: Bladder cancer is the second most common cancer of the urinary tract, however the invasive cystoscopy is still the standard technique for diagnosis and surveillance of bladder cancer. Herein, we radiolabel bladder cancer specific peptide with radioactive iodine ((131/124)I) and evaluate its potential as a new radiopharmaceutical for the non-invasive diagnosis of bladder cancer. A 9-mer bladder cancer specific peptide (BP) was conjugated with tyrosine and cyclized by disulfide bond formation to give Y-BP, which was further radioiodinated to give [(131/124)I]Y-BP in good radiochemical yield. The biodistribution data showed the high selectivity of [(124)I]Y-BP in HT1376 human bladder cancer xenograft models with a tumor-to-muscle ratio of 6.2. This tumor targeting was not observed in control B16F10 melanoma tumor models. In microPET studies, while the control scrambled peptide, [(124)I]Y-sBP, did not accumulate in either the bladder cancer or melanoma, [(124)I]Y-BP showed high tumor uptake only in animals with HT1376 bladder cancer cells. Furthermore, [(124)I]Y-BP showed superior bladder cancer uptake even compared to most commonly used cancer imaging tracer, [(18)F]FDG. The experimental results suggest the potential of [(124)I]Y-BP as a new radiopharmaceutical for the non-invasive diagnosis of bladder cancer with high binding affinity and selectivity.
    Bioorganic & medicinal chemistry 05/2012; 20(14):4330-5. · 2.82 Impact Factor
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    ABSTRACT: Ethylene cross-bridged cyclam with two acetate pendant arms, ECB-TE2A, is known to form the most kinetically stable (64)Cu complexes. However, its usefulness as a bifunctional chelator is limited because of its harsh radiolabeling conditions. Herein, we report new cross-bridged cyclam chelator for the development of ultrastable (64)Cu-radiolabeled bioconjugates. Propylene cross-bridged TE2A (PCB-TE2A) was successfully synthesized in an efficient way. The Cu(II) complex of PCB-TE2A exhibited much higher kinetic stability than ECB-TE2A in acid decomplexation studies, and also showed high resistance to reduction-mediated demetalation. Furthermore, the quantitative radiolabeling of PCB-TE2A with (64)Cu was achieved under milder conditions compared to ECB-TE2A. Biodistribution studies strongly indicate that the (64)Cu complexes of PCB-TE2A cleared out rapidly from the body with minimum decomplexation.
    Bioconjugate Chemistry 02/2012; 23(3):330-5. · 4.82 Impact Factor
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    ABSTRACT: The importance of noninvasive imaging methods to bacterial infections is widely recognized. To obtain bacterial infection imaging with radioisotope-labeled nucleosides, bacterial thymidine kinase (tk) activities of Salmonella typhimurium with [(125)I]5-iodo-1-(2'-fluoro-2'-deoxy-β-d-arabinofuranosyl)uracil ([(125)I]FIAU) or 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) were measured. The infection model in BALB/c mice was imaged with [(125)I]FIAU or [(18)F]FLT using small-animal Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET), respectively. The accumulated radioactivity of [(125)I]FIAU or [(18)F]FLT in the two strains showed a linearly increased pattern with increasing incubation time or bacterial numbers. The image clearly demonstrated a high uptake of [(125)I]FIAU and [(18)F]FLT in the bacterial infection site. [(18)F]FLT uptake in the infection site of was 7.286±2.405, whereas that in the uninfected site was 0.519±0.561. The relative activity ratio of the infected region in relation to the uninfected region was 2.98 at 4h after an injection with [(125)I]FIAU determined by biodistribution data. In conclusion, the bacterial tk activity was confirmed by the cellular uptake and imaging with [(125)I]FIAU or [(18)F]FLT. Therefore, a localized bacterial infection in living mice can be monitored using radioisotope-labeled nucleosides with a nuclear medicine imaging modality.
    International journal of medical microbiology: IJMM 01/2012; 302(2):101-7. · 4.54 Impact Factor
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    ABSTRACT: Nuclear and optical imaging are complementary in many aspects and there would be many advantages when optical imaging probes are prepared using radionuclides rather than classic fluorophores, and when nuclear and optical dual images are obtained using single imaging probe. The luminescence intensities of various radionuclides having different decay modes have been assayed using luminescence imaging and in vitro luminometer. Radioiodinated Herceptin was injected into a tumor-bearing mouse, and luminescence and microPET images were obtained. The plant dipped in [(32)P]phosphate solution was scanned in luminescence mode. Radio-TLC plate was also imaged in the same imaging mode. Radionuclides emitting high energy β(+)/β(-) particles showed higher luminescence signals. NIH3T6.7 tumors were detected in both optical and nuclear imaging. The uptake of [(32)P]phosphate in plant was easily followed by luminescence imaging. Radio-TLC plate was visualized and radiochemical purity was quantified using luminescence imaging. Many radionuclides with high energetic β(+) or β(-) particles during decay were found to be imaged in luminescence mode due mainly to Cerenkov radiation. 'Cerenkov imaging' provides a new optical imaging platform and an invaluable bridge between optical and nuclear imaging. New optical imaging probes could be easily prepared using well-established radioiodination methods. Cerenkov imaging will have more applications in the research field of plant science and autoradiography.
    Nuclear Medicine and Biology 04/2011; 38(3):321-9. · 2.41 Impact Factor
  • Small 12/2010; 6(24):2863-8. · 7.51 Impact Factor
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    ABSTRACT: Fluorescence probes that can detect Aβ (β-amyloid peptide) plaque are important tools for diagnosis of Alzheimer's disease (AD), and 4-N-methylamino-4'-hydroxystilbene (SB-13) is one of the promising candidate molecules. We report here the synthesis of SB-13 derivatives that consist of various electron donating/withdrawing moieties and distinct size of N-substituents. The synthesized compounds were screened for detection of Aβ40 fibrils in vitro. Four compounds exhibited more than sixfold intensity increase, and they were further analyzed for detail bindings and Aβ plaque imaging. Among these molecules, compound 42 meets two critical requirements for imaging agent; high fluorescence responsiveness and strong binding affinity. This compound showed more than 25-fold increase with the dissociation constant of 1.13±0.37μM. In AD mouse brain tissue, 42 selectively stained Aβ plaque, more specifically peripheral regions of Aβ plaque. This finding demonstrated its potential use as brain-imaging agents for AD studies.
    Bioorganic & medicinal chemistry 11/2010; 18(22):7724-30. · 2.82 Impact Factor
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    ABSTRACT: D-[18F]FMAU and L-[18F]FMAU are F-18 labeled nucleoside analogue which have been efficiently synthesized in order to be a PET imaging probe. D-[18F]FMAU and L-[18F]FMAU were compared as PET imaging agents using HSV1-TK gene expressing tumor-bearing mice. Their cellular uptake profiles were also compared using MCA and MCA-TK cell lines. D-[18F]FMAU demonstrated higher cellular uptake and higher accumulation in MCA-TK tumor regions than L-[18F]FMAU. On the other hand, L-[18F]FMAU showed higher MCA-TK/MCA ratio of %ID/g than that of D-[18F]FMAU. L-[18F]FMAU can be utilized as a good candidate for HSV1-TK PET imaging. It can be used for antiviral drug evaluation.
    Bulletin of the Korean Chemical Society 11/2010; 31(11):3309-3312. · 0.84 Impact Factor
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    ABSTRACT: PurposeThe development of a new bifunctional chelator, which holds radiometals strongly in living systems, is a prerequisite for the successful application of disease-specific biomolecules to medical diagnosis and therapy. Recently, TE2A was reported to make kinetically more stable Cu(II) complexes than TETA. Herein, we report a new synthetic route to TE2A and explore its potential as a bifunctional chelator. MethodsTE2A was synthesized using the regioselective alkylation of benzyl bromoacetate and successive deprotection of the methylene bridge and benzyl group. Salt-free TE2A was radiolabeled with 64Cu and microPET imaging was performed to follow the clearance pattern of the 64Cu-TE2A complex. TE2A was conjugated with cyclic RGD peptide and the TE2A-c(RGDyK) conjugate was radiolabeled with 64Cu. ResultsTE2A was prepared in salt-free form from cyclam in an overall yield of 74%. The microPET images showed that 64Cu-TE2A is excreted rapidly from the body by the kidney and liver. TE2A was successfully conjugated with c(RGDyK) peptide through one carboxylate group and the TE2A-c(RGDyK) conjugate was radiolabeled with 64Cu in 94% yield within 30min. ConclusionTE2A can be used by itself as a bifunctional chelator without any further structural modification. KeywordsTE2A-Bifunctional chelator- 64Cu-Conjugation-RGD peptide
    09/2010; 44(3):185-192.
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    ABSTRACT: The goal of this investigation was to evaluate the effects of structural differences between FIAU and FIRU on their ability to serve as a potential tracer for reporter gene imaging. To examine the characteristics of different configurations of FIAU and FIRU, a series of evaluations were done on HSV1-TK gene-expressing cells and on mice with HSV1-TK gene-expressing tumor. The results showed that, as an imaging agent for HSV1-TK-expressing cells, radiolabeled FIAU was more efficient for in vivo imaging than FIRU.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 06/2010; 68(6):971-8. · 1.09 Impact Factor