질문을 형성하며: "음악과 사회"의 연계

( Tia Denora ),최윤실(역) 세계음악학회 2011 음악과 문화 Vol.25 No.-

Effect of PEG chain additive on 6,8-dichloro-2-phenylimidazo[1,2-a] pyridineacetamide (CB185) as a TSPO-binding ligand

Lee, Won Chang,Lee, Sang Hee,Denora, Nunzio,Laquintana, Valentino,Lee, Byung Chul,Kim, Sang Eun 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.2

In our previous studies, we developed a ¹⁸F-labeled TSPO-binding ligand, named [¹⁸F]CB251, which has been proved to be a promising TSPO-binding PET radiotracer for the detection and monitoring of TSPO expression in pathological diseases. (Ki = 0.27 nM for TSPO, 1.96% ID/g of tumor uptake at 1h post-injection) Based on these results, we utilized 6,8-dichloro-2-phenylimidazo[1,2-a]pyridineacetamide analogs, CB185 (1) as a targeting moiety for the selective delivery of probes and anticancer molecules to TSPO-overexpressed tissues. In this study, we designed CB185 derivatives contains different PEG chains (n = 1, 3 and 5) and fluorescence dye (Cy5) to identify the necessary space between a TSPO-binding ligand and an anticancer agent. Three CB185 derivatives (11a-c) which contains Cy5 and PEG chain, were synthesized and the effect of PEG additive on their TSPO-binding affinities were evaluated using in vitro assays. The binding affinity for compounds 11a-c was lower than that of PK11195 (Ki = 3.2 nM), but still characterized by nanomolar binding affinity for TSPO (Ki = 46.5 nM for 11a, 51.0 nM for 11b, and 388.5 nM for 11c). These results showed that the conjugates are characterized by a moderate binding affinity toward TSPO except for compound 11c, which PEG chain consist of five PEG monomers. Our finding might add useful information to decide the appropriate PET chain length for developing new TSPO-targeting drug carriers.

Effect of PEG chain additive on 6,8-dichloro-2-phenylimidazo[1,2-a]pyridineacetamide (CB185) as a TSPO-binding ligand

이원창,Byung Chul Lee,Sang Eun Kim,Sang Hee Lee,Nunzio Denora,Valentino Laquintana 대한방사성의약품학회 2019 Journal of radiopharmaceuticals and molecular prob Vol.5 No.2

In our previous studies, we developed a 18F-labeled TSPO-binding ligand, named [18F]CB251, which has beenproved to be a promising TSPO-binding PET radiotracer for the detection and monitoring of TSPO expressionin pathological diseases. (Ki = 0.27 nM for TSPO, 1.96% ID/g of tumor uptake at 1h post-injection) Basedon these results, we utilized 6,8-dichloro-2-phenylimidazo[1,2-a]pyridineacetamide analogs, CB185 (1) as atargeting moiety for the selective delivery of probes and anticancer molecules to TSPO-overexpressed tissues. In this study, we designed CB185 derivatives contains different PEG chains (n = 1, 3 and 5) and fluorescencedye (Cy5) to identify the necessary space between a TSPO-binding ligand and an anticancer agent. ThreeCB185 derivatives (11a-c) which contains Cy5 and PEG chain, were synthesized and the effect of PEG additiveon their TSPO-binding affinities were evaluated using in vitro assays. The binding affinity for compounds 11a-cwas lower than that of PK11195 (Ki = 3.2 nM), but still characterized by nanomolar binding affinity for TSPO(Ki = 46.5 nM for 11a, 51.0 nM for 11b, and 388.5 nM for 11c). These results showed that the conjugates arecharacterized by a moderate binding affinity toward TSPO except for compound 11c, which PEG chain consistof five PEG monomers. Our finding might add useful information to decide the appropriate PET chain length fordeveloping new TSPO-targeting drug carriers.

Preclinical comparison study between [¹⁸F]fluoromethyl-PBR28 and its deuterated analog in a rat model of neuroinflammation

Moon, Byung Seok,Jung, Jae Ho,Park, Hyun Soo,Contino, Marialessandra,Denora, Nunzio,Lee, Byung Chul,Kim, Sang Eun Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.17

<P><B>Abstract</B></P> <P>We designed and synthesized deuterium-substituted [<SUP>18</SUP>F]fluoromethyl-PBR28 ([<SUP>18</SUP>F]<B>1</B>-<I>d</I> <SUB>2</SUB>) as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced <I>in vivo</I> stability. The comparison studies between [<SUP>18</SUP>F]fluoromethyl-PBR28 ([<SUP>18</SUP>F]<B>1</B>) and its deuterate analog ([<SUP>18</SUP>F]<B>1</B>-<I>d</I> <SUB>2</SUB>) were investigated in terms of <I>in vitro</I> binding affinity, lipophilicity and <I>in vivo</I> stability. In addition, the accuracies of both radioligands were determined by comparing the PET imaging data in the same LPS-induced neuroinflammation rat model. Both aryloxyanilide analogs showed similar lipophilicity and <I>in vitro</I> affinity for TSPO. However, [<SUP>18</SUP>F]<B>1</B>-<I>d</I> <SUB>2</SUB> provided significantly lower femur uptake than [<SUP>18</SUP>F]<B>1</B> (1.5 ± 1.2 <I>vs</I>. 4.1 ± 1.7%ID/g at 2 h post-injection) in an <I>ex vivo</I> biodistribution study. [<SUP>18</SUP>F]<B>1</B>-<I>d</I> <SUB>2</SUB> was also selectively accumulated in the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BP<SUB>ND</SUB> = 3.17 ± 0.48), in a LPS-induced acute neuroinflammation rat model, comparable to that of [<SUP>18</SUP>F]<B>1</B> (BP<SUB>ND</SUB> = 2.13 ± 0.51). These results indicate that [<SUP>18</SUP>F]<B>1</B>-<I>d</I> <SUB>2</SUB> had higher <I>in vivo</I> stability, which resulted in an enhanced target-to-background ratio compared to that induced by [<SUP>18</SUP>F]<B>1</B>.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Deuterated TSPO-binding ligand shows the enhanced <I>in vivo</I> metabolic stability. </LI> <LI> Deuterated analog maintains the biological potency of the parent. </LI> <LI> Enhanced stability leads to promoted target-to-background ratios of PET ligand. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>The comparison studies of brain PET between [<SUP>18</SUP>F]fluoromethyl-PBR28 ([<SUP>18</SUP>F]<B>1</B>) and its deuterate analog ([<SUP>18</SUP>F]<B>1</B>-<I>d</I> <SUB>2</SUB>) were investigated in the same LPS-induced neuroinflammation rat model as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced <I>in vivo</I> stability.</P> <P>[DISPLAY OMISSION]</P>

Assessment of TSPO in a Rat Experimental Autoimmune Myocarditis Model: A Comparison Study between [ ¹⁸ F]Fluoromethyl-PBR28 and [ ¹⁸ F]CB251

Kim, Ga Ram,Paeng, Jin Chul,Jung, Jae Ho,Moon, Byung Seok,Lopalco, Antonio,Denora, Nunzio,Lee, Byung Chul,Kim, Sang Eun MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.1

<P>Overexpression of the 18-kDa translocator protein (TSPO) is closely linked to inflammatory responses in the heart, including myocarditis, which can lead to myocardial necrosis. In vivo assessment of inflammatory responses has enabled the precise diagnosis of myocarditis to improve clinical outcomes. Here, we evaluated TSPO overexpression in a rat model of experimental autoimmune myocarditis (EAM) compared to healthy rats using two TSPO radiotracers, [<SUP>18</SUP>F]fluoromethyl-PBR28 ([<SUP>18</SUP>F]<B>1</B>) and [<SUP>18</SUP>F]CB251 ([<SUP>18</SUP>F]<B>2</B>). All radiolabeling methods were successfully applied to an automated module for the reproducible preparation of TSPO radiotracers. Both radiotracers were directly compared in an EAM rat model, as well as in healthy rats to determine whether either radiotracer provides a more promising assessment of in vivo TSPO overexpression. [<SUP>18</SUP>F]<B>2</B> provided more specific TSPO-uptake in the heart of the EAM rats (1.32-fold that of the heart-to-lung uptake ratio versus healthy controls), while [<SUP>18</SUP>F]<B>1</B> did not show a significant difference between the two groups. Histopathological characterization revealed that a prominent positron emission tomography (PET) signal of [<SUP>18</SUP>F]<B>2</B> in the EAM rats corresponded to the presence of a higher density of TSPO compared to the healthy controls. These results suggest that the imidazole[1,2-a]pyridine-based radiotracer [<SUP>18</SUP>F]<B>2</B> is a sensitive tool for noninvasively diagnosing myocarditis related to inflammation of the heart muscle by assessing abnormal TSPO expression.</P>

Synthesis and Evaluation of Tricarbonyl ^99m Tc-Labeled 2-(4-Chloro)phenyl-imidazo[1,2- <i>a</i> ]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer

Choi, Ji Young,Iacobazzi, Rosa Maria,Perrone, Mara,Margiotta, Nicola,Cutrignelli, Annalisa,Jung, Jae Ho,Park, Do Dam,Moon, Byung Seok,Denora, Nunzio,Kim, Sang Eun,Lee, Byung Chul MDPI 2016 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.17 No.7

<P>The 18-kDa translocator protein (TSPO) levels are associated with brain, breast, and prostate cancer progression and have emerged as viable targets for cancer therapy and imaging. In order to develop highly selective and active ligands with a high affinity for TSPO, imidazopyridine-based TSPO ligand (CB256, <B>3</B>) was prepared as the precursor. <SUP>99m</SUP>Tc- and Re-CB256 (<B>1</B> and <B>2</B>, respectively) were synthesized in high radiochemical yield (74.5% ± 6.4%, decay-corrected, <I>n</I> = 5) and chemical yield (65.6%) by the incorporation of the [<SUP>99m</SUP>Tc(CO)<SUB>3</SUB>(H<SUB>2</SUB>O)<SUB>3</SUB>]<SUP>+</SUP> and (NEt<SUB>4</SUB>)<SUB>2</SUB>[Re(CO)<SUB>3</SUB>Br<SUB>3</SUB>] followed by HPLC separation. Radio-ligand <B>1</B> was shown to be stable (>99%) when incubated in human serum for 4 h at 37 °C with a relatively low lipophilicity (log<I>D</I> = 2.15 ± 0.02). The rhenium-185 and -187 complex <B>2</B> exhibited a moderate affinity (<I>K</I><SUB>i</SUB> = 159.3 ± 8.7 nM) for TSPO, whereas its cytotoxicity evaluated on TSPO-rich tumor cell lines was lower than that observed for the precursor. In vitro uptake studies of <B>1</B> in C6 and U87-MG cells for 60 min was found to be 9.84% ± 0.17% and 7.87% ± 0.23% ID, respectively. Our results indicated that <SUP>99m</SUP>Tc-CB256 can be considered as a potential new TSPO-rich cancer SPECT imaging agent and provides the foundation for further in vivo evaluation.</P>

The position of fluorine in CP-118,954 affects AChE inhibition potency and PET imaging quantification for AChE expression in the rat brain

Lee, Byung Chul,Moon, Byung Seok,Park, Hyun Soo,Jung, Jae Ho,Park, Hyun Sik,Park, Do Dam,de Candia, Modesto,Denora, Nunzio,Altomare, Cosimo D.,Kim, Sang Eun Elsevier 2017 European journal of pharmaceutical sciences Vol.109 No.-

<P><B>Abstract</B></P> <P>The <I>in vitro</I> inhibition potency against acetylcholinesterase (AChE) of fluorinated derivatives of CP-118,954 (<B>1</B>) has been shown to depend upon the position of aromatic fluorine (F) substitution on the <I>N</I>-benzyl moiety. Indeed, the <I>meta</I>-F-substituted compound <B>3</B> (IC<SUB>50</SUB> =1.4nM) shows similar potency with the parent compound <B>1</B> (IC<SUB>50</SUB> =1.2nM), whereas the <I>ortho</I>-F derivative <B>2</B> (IC<SUB>50</SUB> =3.2nM) and <I>para</I>-F derivative <B>4</B> (IC<SUB>50</SUB> =10.8nM) were found to be less potent AChE inhibitors. A comparative <I>in vivo</I> microdialysis study in rats showed that <B>3</B> has the strongest effect on the neuropharmacological properties as AChE inhibitor. For PET imaging studies, a radiolabeled ligand ([<SUP>18</SUP>F]<B>3</B>) was synthesized through nucleophilic aromatic substitution reaction of diaryliodonium salt-based aldehyde precursor followed by reductive alkylation in a two-step radiolabeling procedure with 11.5 ± 1.2% (<I>n</I> =24, non-decay corrected) radiochemical yield and over 99% radiochemical purity. In a comparative PET imaging study of the three <SUP>18</SUP>F-containing derivatives of CP-118,954 ([<SUP>18</SUP>F]<B>2</B>–<B>4</B>), [<SUP>18</SUP>F]<B>3</B> showed the highest radioactivity in the AChE-rich region of normal rat brain which visually reflected the <I>in vitro</I> AChE-binding affinity of <B>3</B>. These findings support [<SUP>18</SUP>F]<B>3</B> as a promising AChE-targeted PET imaging ligand for the assessment of cholinergic activity into the brain, providing also insights into the AChE ligand disposition, which depends upon the position of the aromatic fluorine in the benzyl moiety.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>