Derivatives of Dibenzothiophene for Positron Emission Tomography Imaging of α7-Nicotinic Acetylcholine Receptors

Abstract

A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for α7-nicotinic acetylcholine receptors (α7-nAChRs) (Ki = 0.4 – 20 nM) has been synthesized for PET imaging of α7-nAChRs. Two radiolabeled members of the series [18F]7a (Ki = 0.4 nM) and [18F]7c (Ki = 1.3 nM) were synthesized. [18F]7a and [18F]7c readily entered the mouse brain and specifically labeled α7-nAChRs. The α7-nAChR selective ligand 1 (SSR180711) blocked the binding of [18F]7a in the mouse brain in a dose-dependent manner. The mouse blocking studies with non-α7-nAChR CNS drugs demonstrated that [18F]7a is highly α7-nAChR selective. In agreement with its binding affinity the binding potential of [18F]7a (BPND = 5.3 – 8.0) in control mice is superior to previous α7-nAChR PET radioligands. Thus, [18F]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of α7-nAChR in non-human primates.

Development of [ 18 F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography

“…The binding assay of all four compounds was performed under the same assay conditions (Table 2). This head-to-head comparison demonstrated that the α7-nAChR affinity of ASEM is 1-2 orders of magnitude superior to the previous radiotracers[48] and in vivo specific binding of [ 18 F]ASEM was expected to be proportionally greater.…”

“…As summarized in the recent reviews[35, 46-48], those efforts did not lead to an α7-nAChR PET radioligand with sufficient in vivo specificity.…”

“…3), exhibited some specific binding in the brains of lab animals, but their specificities were also insufficient for human PET. The main reason for the deficient PET properties of most of the initial radioligands was due to the low binding affinity of these compounds (see for review[48]). Another recent PET tracer [ 11 C]A752274 (Fig.…”

“…PET chemists from JHU synthesized a series of fluoro-derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[ b , d ]thiophene 5,5-dioxide. Within the series, 4-(6- fluorodibenzo[b,d]thiophen-3-yl)-1,4-diazabicyclo[3.2.2]nonane 5,5-dioxide (JHU82132, ASEM) and its para -isomer (JHU82108, para -ASEM) exhibited the best α7-nAChR in vitro binding affinity and high selectivity vs. heteromeric nAChR subtypes or 5-HT 3 [48, 59] (see Table 1). The abbreviation “ASEM” stands for ALPHA-SEVEN (Α-СЕМЬ) in Greek-Russian as was suggested by Dr. R.F.…”

“…The final radiolabeled products were purified by preparative high-performance liquid chromatography (HPLC) and solid-phase extraction and formulated as sterile apyrogenic solutions in 7% ethanolic saline. Both radiotracers, [ 18 F]ASEM and para - [ 18 F]ASEM, were prepared with comparable radiochemical yields of 16 ± 6% (n=14) (non-decay-corrected), specific radioactivities in the range of 330 - 1260 GBq/μmol (9-34 Ci/μmol), and a radiochemical purity greater than 99%[48]. …”