Synthesis and β-amyloid binding properties of rhenium 2-phenylbenzothiazoles

Abstract

As a first step toward the development of 99m Tc PiB analogs, we have synthesized six neutral Re 2-phenylbenzothiazoles via pendant or integrated approach. These Re compounds bind to Aβ 1-40 fibrils with fairly good affinities (K i = 10.0-88.6 nM) and have moderate lipophilicities (logP C18 = 1.21-3.26). The Re compounds prepared via the integrated approach are smaller in size, and therefore their corresponding 99m Tc analogs would have a greater chance of crossing the blood-brain barrier well. For potential clinical applications, further optimization on the structure-activity relationship to obtain Re 2-phenylbenzothiazoles with higher binding affinities (<10 nM) might be needed. The integrated approach reported here to obtain neutral, compact and lipophilic Re 2-phenylbenzothiazoles could to be applied to other high affinity pharmacophores as well as to generate 99m Tc analogs that could hold promise for extending the use of Aβ imaging in living human brain to many more clinical settings because they could be used with SPECT. KeywordsTechnetium-99m; Rhenium; SPECT; PiB; β-Amyloid plaques; Alzheimer's disease Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder characterized by irreversible memory impairment, continuous cognitive decline and behavioral disturbances. The production and accumulation of β-amyloid peptides (Aβ) is believed to be pivotal to the pathogenesis and progression of AD 1 , and the formation of Aβ plaques precedes the appearance of clinical symptoms. 2 Research on the treatment of AD has focused on the anti-amyloid strategy and currently there are more than 10 anti-amyloid drugs in phase 1 to phase 3 clinical trials. 3 The development of Aβ plaque targeting radiotracers has enabled non-invasive imaging and quantification of Aβ deposition in living human brain. This technology could provide a useful tool for identifying preclinical cases of AD as candidates for early intervention and to follow the effectiveness of anti-amyloid therapy in individual patients. Among Aβ imaging agents 4-9 currently under clinical evaluation, 2-(4-[ 11 C]methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B, PiB) 5 has achieved highest signal-to-noise ratio, and has been adopted to perform AD-related research studies at more than 40 research centers worldwide. Unfortunately, due to its short half-life (20 min) the 11 C label on PiB limits its use to major academic PET (positron emission tomography) facilities with on-site cyclotrons and sophisticated radiochemistry laboratories. Derivatives of PiB 8 labeled with the longer halflife (110 min) radioisotope 18 F have recently been developed and could increase the availability of Aβ imaging to all PET facilities, but this still represents a minority of modern hospitals, as only a small fraction of hospitals have a PET scanner. However, many more hospitals have the Compound 1 (Table 1) was synthesized in three steps from 2-(4-dimethylaminophenyl)-6-hydroxybenzothiazole 19 as illustrated in Scheme 1. The dimethylamino subst...

Design, synthesis and structure–activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents

“…The aliphatic amino N-H group that has relatively higher pKa value was not deprotonated after Re complexation reaction, and therefore, the overall charge was balanced. These results were consistent with our previously reported results for the synthesis of 12 and 21 17 .…”

“…In order to obtain neutral Tc/Re complexes, we also added one small methyl group to one of the aliphatic amino groups. After such modification (see Scheme 1A), all three protons were lost after complexation with [Re(V)O] 3+ , and the overall charge of 2-ABT 1–5 was balanced, which is in agreement with our previously reported results from the synthesis of 6 17 .…”

“…In contrast to most attempts by other investigators on the development of 99m Tc-labeled 2-ABTs using the pendant approach 14–16 , we have previously demonstrated the feasibility of design and synthesis of three neutral and lipophilic Re (as a surrogate of 99m Tc) 2-ABTs (compounds# 6 , 12 and 21 in Table 1) with moderate Aβ binding affinity (30–87 nM) using the integrated approach to minimize their overall molecular weight (<550 daltons) 17 . Compound 6 was prepared using a thiol-triamine SN 3 tetradentate chelator (Scheme 1A), while semi-rigid thiol-diamine-phenol (SN 2 O) and thiol-diamine-thiol (SN 2 S) chelators (Scheme 1B, X= O and S) were used for the preparation of 12 and 21 , respectively.…”

Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain

“…Because of the fast brain and plasma clearance observed in AD and in healthy subjects, the in vivo metabolism and instability of 123 I-IMPY may not provide an optimal signal-to-noise ratio. Additional candidates are being explored for SPECT of Aβ plaques in the brain (22,23). …”

Enaminonitrile in heterocyclic synthesis: Synthesis and antimicrobial evaluation of some new pyrazole, isoxazole and pyrimidine derivatives incorporating a benzothiazole moiety

“…Elnagdi et al have reported several novel syntheses of azoles, azines, and azoloazines utilizing enaminonitriles as starting components [7][8][9]. On the other hand, the considerable biological and medicinal activities of benzothiazoles initiated considerable recent interest in the development of syntheses of these molecules [10][11][12][13][14][15][16][17][18]. In continuation of our interest in the synthesis of heterocycles containing a benzothiazole moiety [19,20], to identify new candidates that may be value in designing new, potent, selective and less toxic antimicrobial agents, we reported here a facial synthesis of some new pyrazole, isoxazole and pyrimidine derivatives pendant to a benzothiazole via the reactions of enaminonitrile with some nitrogen nucleophiles.…”