¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

Abstract

The α7-nicotinic cholinergic receptor (α7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for α7-nAChR are suitable for quantitative PET imaging, mostly due to insufficient specific binding. The goal of this study was to evaluate the potential of [18F]ASEM ([18F]JHU82132) as an α7-nAChR radioligand for PET. Methods Inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of [18F]ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET). Results ASEM is an antagonist for the α7-nAChR with high binding affinity (Ki = 0.3 nM). [18F]ASEM readily entered the baboon brain and specifically labeled α7-nAChR. The in vivo specific binding of [18F]ASEM in the brain regions enriched with α7-nAChRs was 80–90%. SSR180711, an α7-nAChR selective partial agonist, blocked [18F]ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of [18F]ASEM was mediated by α7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for [18F]ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus) and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential (BPND) values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of [18F]ASEM and α7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous post-mortem human data. Conclusion [18F]ASEM holds promise as a radiotracer with suitable imaging properties for quantification of α7-nAChR in the human brain.

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

“…Based on the favorable imaging properties identified in control CD1 mice, the [ 18 F]ASEM binding was investigated in DISC1 mice. In agreement with the reduced density of α7-nAChRs in the brain tissue of schizophrenic subjects, the [ 18 F]ASEM binding in the α7-nAChR – rich brain regions was significantly lower in the DISC1 mice when compared to control animals (data not shown, see paper[59]). This result emphasizes the potential utility of [ 18 F]ASEM for imaging of α7-nAChRs in schizophrenia.…”

“…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 HPLC analysis of blood samples from CD-1 mice, and, also, from baboons[59] and human subjects[68] demonstrated that the parent compound [ 18 F]ASEM was gradually metabolized to the same hydrophilic radiometabolites in all three species. Luckily, only a small fraction of [ 18 F]ASEM radiometabolites penetrates the blood-brain barrier and the main radioactive compound in the brain is the parent [ 18 F]ASEM (>95%), as it is shown by the HPLC analysis of the mouse brain tissue.…”

“…Luckily, only a small fraction of [ 18 F]ASEM radiometabolites penetrates the blood-brain barrier and the main radioactive compound in the brain is the parent [ 18 F]ASEM (>95%), as it is shown by the HPLC analysis of the mouse brain tissue. Because the radiometabolite fraction in the brain tissue is insignificant, mathematical PET modeling of the radiometabolites is not necessary for quantification of α7-nAChRs with [ 18 F]ASEM [59]. …”

“…The successful brain distribution studies of [ 18 F]ASEM in rodents (see above) provided a foundation for further pre-clinical evaluation in baboons [59]. The main purpose of these studies was to determine if (1) [ 18 F]ASEM exhibits the brain regional distribution that matches the distribution of α7-nAChRs in non-human primates; (2) the binding is α7-nAChR specific; (3) the brain pharmacokinetics of [ 18 F]ASEM are suitable for quantification of α7-nAChRs and (4) to evaluate the PET imaging characteristics of [ 18 F]ASEM by mathematical modeling methods.…”