Jung Young Kim

Luminescence imaging using radionuclides: a potential application in molecular imaging☆

INTRODUCTIONnNuclear 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.nnnMETHODSnThe 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.nnnRESULTSnRadionuclides 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.nnnCONCLUSIONnMany 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.

Biarylpyrazolyl Oxadiazole as Potent, Selective, Orally Bioavailable Cannabinoid-1 Receptor Antagonists for the Treatment of Obesity

Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.

Revival of TE2A; a better chelate for Cu(II) ions than TETA?

A highly effective synthetic route for TE2A was developed and the (64)Cu-labeled TE2A complexes showed higher kinetic inertness and faster clearance than most commonly used TETA analogs.

Effect of repetitive transcranial magnetic stimulation in a patient with chronic crossed aphasia: fMRI study.

OBJECTIVEnWe report here the case of a 52-year-old Korean woman who was initially diagnosed with non-fluent/global crossed aphasia.nnnMETHODS AND RESULTSnInitial computed tomography of the brain revealed a haematoma of approximately 40 ml in the right basal ganglia area and cavitation around the right lateral ventricle. Three years after onset the aphasia was resolved to a conduction aphasia and she had an ongoing left-sided gait disturbance. Follow-up anatomical magnetic resonance imaging found no recurrence of haemorrhage. Language functional magnetic resonance imaging was examined before and after repetitive transcranial magnetic stimulation treatment. A 90-mm round coil stimulator was used and the repetitive transcranial magnetic stimulation treatment location was P3 on the 10-20 International electrode placement system (1 Hz, 20 min per day for 10 days over a 2-week period). Functional magnetic resonance imaging results before repetitive transcranial magnetic stimulation treatment showed no significant activity in either the ipsilesional or contralesional hemispheres for noun generation and sentence completion paradigms (p < 0.001, cluster size 128). Compared with the pre-treatment phase, following repetitive transcranial magnetic stimulation treatment the data from functional magnetic resonance imaging revealed significant activations in the right inferior frontal lobe (Brocas area), posterior temporal gyrus (Wernickes area), and parietal lobe for both the noun generation and sentence completion tasks (p < 0.001, cluster size 128).nnnCONCLUSIONnThis functional magnetic resonance imaging case study is the first to suggest the use of repetitive transcranial magnetic stimulation for improving language outcome in a patient with crossed aphasia. In addition, we report the value of language functional magnetic resonance imaging before and after repetitive transcranial magnetic stimulation treatment for determining the effect of treatment and the underlying neurobiological mechanism of functional recovery following repetitive transcranial magnetic stimulation treatment.

New macrobicyclic chelator for the development of ultrastable 64Cu-radiolabeled bioconjugate.

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.

A simple Cu-64 production and its application of Cu-64 ATSM.

One of the positron emission radionuclides, (64)Cu, has been reported to be a particularly effective radioisotope in PET imaging study. This utility of (64)Cu depends on the chemical stability in water with proper energy and half-life as gamma-emitters. Hence, we tried to develop a simple method for producing this isotope using an old cyclotron model in our site (50MeV, Scantronics co.). In particular, we designed the equipments of enrich (64)Ni plating system and radioactive (64)Cu separation using plastic cartridge column; (64)Ni plating system on gold foil which located in the 13 degrees angle target toward beam irradiation. For the nuclear reaction of (64)Cu, it was applied to (64)Ni(p, n) (64)Cu at low energy under the degrader composed of Al and Ta foils. After beam irradiation, (64)Cu was identified by multichannel analyzer installed for a HPGe detector and its utility was certified by the microPET images of (64)Cu-ATSM (CT-26 tumor bearing mouse as reported previously). The image quality of (64)Cu was also very similar to that of (18)F radioisotope in microPET scanner. In conclusion, a method of (64)Cu production and its application was successfully established in old cyclotron having high energy.

Propylene Cross-Bridged Macrocyclic Bifunctional Chelator: A New Design for Facile Bioconjugation and Robust 64Cu Complex Stability

The first macrocyclic bifunctional chelator incorporating propylene cross-bridge 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 a robust Cu complex. The cyclic RGD peptide conjugate of PCB-TE2A-NCS was prepared and successfully radiolabeled with (64)Cu 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.

Gadolinium Complex of 125I/127I-RGD-DOTA Conjugate as a Tumor-Targeting SPECT/MR Bimodal Imaging Probe

The work describes the synthesis and in vivo application of [Gd(L)(H2O)]·xH2O, where L is a ((125)I/(127)I-RGD)- DOTA conjugate, as a tumor-targeting SPECT/MR bimodal imaging probe. Here, ((125)I/(127)I-RGD)-DOTA signifies a cocktail mixture of radioisotopic (1a, L = (125)I-RGD-DOTA) and natural (1b, L = (127)I-RGD-DOTA) Gd complexes. The two complexes are chemically equivalent as revealed by HPLC, and their cocktail mixture exhibits the integrin-specific tumor enhancement, demonstrating that they constitute essentially a single bimodal imaging probe. Employment of a cocktail mixture thus proves to be a sole and practical approach to overcome the sensitivity difference problem between MRI and SPECT.

Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination.

Introduction: [18F]MeFWAY has been developed for imaging the serotonin 1A receptors in the brain. The purpose of this study were to verify the metabolic stability of [18F]MeFWAY, to measure the degree of defluorination of [18F]MeFWAY in vivo, to investigate methods of inhibition of defluorination of [18F]MeFWAY, and to assess the efficacy of [18F]MeFWAY in rat brains in vivo. Methods: MicroPET experiments in rats were conducted to confirm the distribution of radioactivity in the brain. Nondisplaceable binding potential (BPND) in the hippocampus and frontal cortex were also analyzed. Miconazole and fluconazole were tested for the ability to suppress defluorination of [18F]MeFWAY. We conducted a blockade and displacement experiment by treating with WAY‐100635. Results: In vitro stability tests showed that MeFWAY was very stable in serum for 6 h, but PET revealed that authentic [18F]MeFWAY underwent significant defluorination in vivo. In vitro inhibition study against decreasing parent activity in liver microsomes, miconazole and fluconazole suppressed metabolic elimination of MeFWAY. However, in the PET study, fluconazole showed more potent inhibitory activity than miconazole. In the suppression of metabolizing enzymes using fluconazole, radioactivity in skull was dramatically decreased by 81% (compared with 69% with miconazole) and it was coupled with an increase in brain uptake. Moreover, BPND in hippocampus was 5.53 and 2.66 in frontal cortex. The blockade and displacement study showed the specificity of [18F]MeFWAY to 5‐HT1A receptors. Conclusion: In the rat brain, [18F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole. Synapse, 2012.

Heteronuclear Gd-99mTc Complex of DTPA-Bis(histidylamide)Conjugate as a Bimodal MR/SPECT Imaging Probe

The work describes the synthesis and in vivo application of heterotrimetallic complexes of the type {Gd(H2O)[(M(H2O)(CO)3)2(1)]} {1 = DTPA-bis(histidyl-amide); M = Re (3a); (99m)Tc (3b)} for dual modality MR/SPECT imaging. Here, the DTPA-bis(histidylamide) conjugate functions as a trinucleating chelate incorporating Gd in the DTPA core with Re or (99m)Tc in the pair of histidylamide side arms. The two complexes are chemically equivalent as revealed by HPLC, and their cocktail mixture (3a + 3b) has demonstrated itself to be essentially a single bimodal imaging probe. The present system has thus overcome the sensitivity difference problem between MRI and SPECT and paved the way for practical applications.