title: Synthesis, conjugation and relaxation studies of gadolinium(III)-4-benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent.
abstract: Magnetic resonance (MR) imaging is widely used in clinical research to map the structural and functional organization of the brain. We have designed and synthesized a Gd-based specific MR contrast agent that binds to regions in the brain. The presented compound {4-[(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-7,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl} acetic acid (DO3A-BT) was synthesized by conjugating the chloroacetylated product of 4-benzothiazol-2-yl-phenylamine with a trisubstituted cyclen. The lanthanide complex (Ln-DO3A-BT) was evaluated in vitro for both MR (Gd-DO3A-BT) and optical (Eu-DO3A-BT) imaging applications. The complex Gd-DO3A-BT displays a relaxivity of r1 = 4.18 mM(-1) s(-1) at 4.7 T which is 1.2 times greater than Dotarem and significantly higher than the brain specific MR contrast agent Luxol Fast Blue (LFB). The protonation constant of the ligand (pKa1 = 9.91, pKa2 = 8.22, pKa3 = 5.01) and the stability constant of the complex formed between Gd(III), Eu(III) and Ca(II) and ligand DO3A-BT (log βGdL = 18.4, log βEuL = 18.3, log βZn2L = 7.1, log βCa2L = 6.3) were recorded by potentiometric titration. The constants reflect the high stability of the ligand with lanthanides compared with endogenous metal ions. The transmetalation stability of Gd-DO3A-BT toward Zn proved to be excellent with a rate constant of 3.07 × 10(-5) s(-1) which is in line with other tetraazatetraacetic acid (DOTA)-monoamide complexes. The hydration number (q) was found to be 0.92, and is calculated from the difference in the luminescence lifetime of Eu-DO3A-BT in H2O and D2O solutions to determine the coordination state of this complex. The in vivo biodistribution of (99m)Tc-DO3A-BT in BALB/c mice showed a brain uptake of 1.2% ID g(-1) at 2 min post injection when injected with mannitol which disrupts the blood-brain-barrier (BBB) due to osmotic shock. In vitro binding on the brain homogenate revealed a high uptake by the neuronal/glial cells for in vivo applications.
authors: Division of Cyclotron and Radio-Pharmaceutical Sciences, Institute of Nuclear medicine and allied sciences, Brig S. K. Majumdar Road, Delhi-54, India.
authors: Nisha
authors: N
authors: Saini
authors: Raunak
authors: R
authors: Varshney
authors: Anjani K
authors: AK
authors: Tiwari
authors: Ankur
authors: A
authors: Kaul
authors: Michele
authors: M
authors: Allard
authors: M P S
authors: MP
authors: Ishar
authors: Anil K
authors: AK
authors: Mishra
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging; D003287:Contrast Media / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004355:Drug Stability; D005682:Gadolinium / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D011877:Radionuclide Imaging; D013667:Technetium / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000814:Aniline Compounds; D052160:Benzothiazoles; D003287:Contrast Media; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D013667:Technetium; D005682:Gadolinium; C005465:benzothiazole