A Phenylbenzothiazole Conjugate with the Tricarbonyl fac‐[M(I)(CO)₃]⁺ (M = Re, ⁹⁹Tc, ^99mTc) Core for Imaging of β‐Amyloid Plaques

Abstract

The 2-(4Ј-aminophenyl)-6-methylbenzothiazole that is known to display affinity and specificity toward the amyloid plaques of Alzheimer's disease (AD) has been joined to the tricarbonyl [M(CO) 3 NNO] chelate (M = Re, 99 Tc, and 99m Tc) through a five-carbon linker chain to generate the neutral complex 1 (namely, Re-1 for M = Re; 99 Tc-1 for M = 99 Tc; and 99m Tc-1 for M = 99m Tc) with the aim of developing a singlephoton emission computed tomography (SPECT) radiodiagnostic agent for AD. Re-1 was characterized by spectroscopic methods and X-ray crystallography, whereas the detailed4279 NMR spectroscopic analysis of 99 Tc-1 demonstrated its structural similarity to Re-1. Complexes Re-1 and 99 Tc-1 display selective binding affinity for amyloid plaques as evidenced by fluorescence spectroscopy, whereas the biodistribution data of 99m Tc-1Ϫcharacterized by relatively low brain uptake, fast clearance from brain and blood, and in vivo sta-bilityϪare considered encouraging for further elaboration on the structural features of 1 in the direction of increased brain uptake.Aβ plaques in living brain tissue [7][8][9] and demonstrated the potential utility of these agents. The most widely studied PET amyloid imaging agent is the 2-phenylbenzothiazole derivative 2-(4Ј-[ 11 C]methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh compound-B, [ 11 C]PiB), a neutral derivative of the amyloid binding dye thioflavin-T (Scheme 1) that is employed in clinical practice. The histological and Scheme 1. Structures of thioflavin T, Pittsburg compound B (PiB), and complex 1.www.eurjic.org

Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer's disease

“…Brain uptake of [ 99m Tc(CO) 3 L 20 ] administered through tail vein injection to Swiss Albino mice showed moderate brain uptake at 1 minute post injection (0.69% ID per g) combined with fast clearance (0.05% ID per g 15 min post injection; 0.02% ID per g 60 min post injection). 103 Selected substituted chalcones have a conjugated planar structure and bind to Ab plaques. Replacement of a phenyl ring with a cyclopentadienyl functional group allows the synthesis of ''piano stool'' type complexes [CpM(CO) 3 ] (where Cp = cyclopentadienyl and M = Re I or Tc I ).…”

99Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

“…Furthermore, the β ‐emitting radioisotopes of Tc, 99 Tc (t 1/2 =2.12 × 105 years, E max = 0.29 MeV) are similar to radioisotopes of rhenium 186 Re (E max = 1.07 MeV) and 188 Re (E max = 2.12 MeV) that also are β ‐emitting, which are already used in nuclear medicine for radiotherapy applications . The previous studies of NMR spectroscopy, involving the research group of Pelecanou et al ., point out that Tc and Re complexes present similar structural properties …”

“…Recent studies show that the radioisotopes of Tc are promising nuclei for applications involving NMR and magnetic resonance images techniques . According to Bühl and Golubnychi, 99 Tc NMR spectroscopy can be used as a powerful spectroscopic technique used for characterization of Tc complexes, because the δ ( 99 Tc) values cover a large chemical‐shift range (ca 9000 ppm) and can be very sensitive to slight variations in geometric and electronic parameters .…”

Synthesis of Oxorhenium(V) and Oxotechnetium(V) Complexes That Bind to Amyloid-β Plaques

“…The [Re­(CO) 3 ] + analogues formed with these ligands bound to Aβ plaques in post-mortem human tissue, but the brain uptake of the [Tc­(CO) 3 ] + complexes was relatively low . Others have also reported low brain uptake for several complexes designed to bind to amyloid plaques featuring the organometallic [Tc­(CO) 3 ] + core. − In this paper, we describe the synthesis of tetradentate trianionic ligands designed to form charge-neutral complexes with [TcO] 3+ cores and prepare a derivative featuring a styrylpyridyl functional group designed to bind to Aβ plaques. A similar integrated approach of incorporating the Aβ plaque binding functional group into tetradentate ligands designed to bind to positron-emitting isotopes of copper led to complexes that displayed good interactions with Aβ plaques and crossed the blood–brain barrier .…”