Journal of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회지)

Korean Society of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회)
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Synthesis and biological evaluation of tricarbonyl technetium labeled 2-(4-chloro)phenyl-imidazo[1,2-a]pyridine analog (99mTc-CB257) as a TSPO-binding ligand

  • Choi, Ji Young (Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University) ;
  • Jung, Jae Ho (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Song, In Ho (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Moon, Byung Seok (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Lee, Byung Chul (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Kim, Sang Eun (Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University)
  • Received : 2018.12.12
  • Accepted : 2018.12.21
  • Published : 2018.12.30
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Abstract

In our previous study, tricarbonyl $^{99m}Tc$-labeled TSPO-binding ligand, named $^{99m}Tc$-CB256, having positively charge (+1) was investigated but did not show promising results in in vivo environment despite of a nanomolar binding affinity for TSPO. Because the overall positively charge of $^{99m}Tc$-CB256 would likely interrupt its target protein uptake, we herein designed the neutral tricarbonyl-$^{99m}Tc$ labeled TSPO-binding ligand ($^{99m}Tc$-CB257, 1). $^{99m}Tc$-CB257 was prepared by the facile incorporation of the $[^{99m}Tc(CO)_3]^+$ into a N-(hydroxycarbonylmethyl)-2-picoly moiety in CB257. The radiochemical yield of $^{99m}Tc$-CB257 after HPLC purification was $54.1{\pm}2.4%$ (decay corrected, n = 3). The authentic Re-CB257 (2) was synthesized by using $(NEt_4)_2[Re(CO)_3Br_3]$ in 69.0% yield. The binding affinity of 2 for TSPO was measured in leukocyte and showed approximately 280 times higher than that observed for the positively charged (+1) ligand, Re-CB256 ($K_i=0.57{\pm}0.06nM$ versus $159.3{\pm}8.7nM$, respectively). Our results indicated that 1 can be considered potentially as a new SPECT radiotracer for TSPO-rich cancer and provides the foundation for further in vivo evaluation related with abnormal TSPO-overexpression environments.

Keywords

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Figure 1. Structure of 99mTc- or Re-CB256 and 99mTc- or Re-CB257

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Scheme 1. Synthesis of CB257 (3), 99mTc- (1) and Re-CB257 (2). Reagents and conditions: a) (i) N-(2-carboxylmethyl)-N-(2-pyridinylmethyl)-1,1-dimethylethylester-glycine, K2CO3, THF, r.t, 16 h, (ii) TFA:CH2Cl2, r.t, 4 h; b) (Net4)2[ReBr3(CO3)], MeOH, 80 ℃, 1 h for 2 and [99mTc(CO)3(H2O)3]+, MeOH:saline (v/v = 1/1), 80 ℃, 20 min for 1.

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Figure 2. Coinjection HPLC profile of 99mTc-CB257 (1) and Re-CB257 (2). (A) gamma-ray spectrum. (B) UV spectrum (254 nm).

Table 1. Affinity (Ki/nM) of 2 for TSPO by using the separated leukocytes in human blooda.

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