Advances in PET Imaging of α7 Nicotinic Receptors: From Radioligand Development to CNS Applications

ABSTRACT

Positron emission tomography (PET) has significantly advanced our understanding of the brain by enabling non‐invasive imaging and quantification of molecular processes, including receptor binding. In this review, we explore the development and application of PET radioligands targeting the α7 nicotinic acetylcholine receptor (α7 nAChR), a receptor implicated in various central nervous system (CNS) diseases, such as Alzheimer's disease, schizophrenia and cognitive disorders. Despite challenges associated with the low density of α7 nAChRs and difficulties in achieving adequate brain penetration, several promising radioligands have been developed, including ¹¹C‐(R)‐MeQAA, ¹¹C‐NS14492 and ¹⁸F‐ASEM. These radioligands facilitate the evaluation of the ‘three pillars of survival’ in drug development: tissue accessibility, target engagement and downstream pharmacology. PET imaging offers critical insights into drug distribution across the blood–brain barrier, receptor occupancy and the pharmacodynamic effects of α7 nAChR–targeted therapies. By reviewing current radioligands and their applications, we highlight the potential of PET imaging to deepen our understanding of α7 nAChR–mediated signalling pathways and its implications for CNS drug discovery. Future innovations in radioligand development, including more selective and brain‐penetrant compounds, will be key to fully realizing the potential of PET imaging in α7 nAChR–targeted research and treatment.

Summary.

• The α7 nicotinic acetylcholine receptor (α7 nAChR) plays a crucial role in brain functions related to memory and thinking.

• This review looks at how drugs designed to stimulate these receptors may help treat cognitive issues in Alzheimer's disease and schizophrenia.

• Over the years, many drugs have been developed and tested in clinical trials, but most have failed to show lasting improvements in memory or thinking skills.

• The review discusses possible reasons for these failures and explores new strategies, such as better trial designs and combination therapies, which could improve future treatments targeting these receptors.

1. Introduction

Positron emission tomography (PET) is a non‐invasive imaging technique that has revolutionized our understanding of the brain by allowing visualization and quantification of molecular processes like metabolism, neurotransmitter release and receptor binding. The principle of PET imaging is the detection of positron‐emitting isotopes such as carbon‐11, fluorine‐18 and bromine‐76. These isotopes are introduced into the body through intravenous (IV) injection of a tracer molecule, referred to as a radioligand when targeting a receptor, and are carried to the target organ via the bloodstream. The radioligand is administered in low mass amounts to image the function of targets without altering them pharmacologically. As isotopes decay, they emit positrons that travel a short distance before colliding with electrons in surrounding tissue, leading to annihilation and the production of two 511‐keV gamma rays emitted in opposite directions [1]. These gamma rays are captured by detectors arranged around the subject. The nearly perfect 180° emission allows for localization of the positron and its target through a line of response (LOR), with the position calculated using the relative delay in detection [2] (Figure 1). Multiple LORs are generated during a scan, and computer algorithms reconstruct the data into a 3D quantitative distribution of the tracer after correcting for absorption, scatter and random coincidence.

FIGURE 1.

PET scan principles: a proton decays into a neutron, emitting a positron, which then encounters an electron. Their annihilation produces two 511‐keV photons travelling in opposite directions. These photons are detected by a ring of detectors, defining a line of response (LOR) for image reconstruction.

Despite its many advantages, PET imaging has limitations. One major issue is the high cost and limited availability of scanners and radiotracers, along with logistical challenges [3]. Another limitation is the low spatial resolution, which ranges from 4 to 5 mm in clinical scanners to ~2.5 mm in brain‐specific tomographs [4]. Given the relatively low spatial resolution of PET images, the technique is frequently combined with high‐resolution methods like MRI or CT to integrate anatomical and biological data. Promisingly, new ultra‐high performance PET imaging systems for the human brain are being developed, offering approximately 1‐mm resolution [5].

2. PET Imaging Applications in Drug Development

Over the past few decades, scientific advancements have led to the creation of tools that enhance drug discovery, including the use of PET imaging for receptor‐targeted therapies. Despite these developments, the pharmaceutical industry continues to face challenges, particularly in developing treatments targeting central nervous system (CNS) receptors, such as α7 nicotinic acetylcholine receptors (α7 nAChRs), which are implicated in neurodegenerative diseases and cognitive dysfunction [6].

To address these challenges, the framework of the ‘three pillars of survival’—tissue accessibility, target engagement and demonstration of downstream pharmacology [7]—can provide valuable insights for developing α7 nAChR–targeted therapies. The unique properties of α7 nAChRs, including their low density and complex distribution in the brain, require a specific focus on these three pillars when considering PET imaging as a tool for drug development.

3. PET Imaging for Evaluating Tissue Accessibility

Assessing whether a drug candidate can cross the blood–brain barrier (BBB) and reach α7 nAChRs is a critical early step in CNS drug development. The low density of α7 nAChRs in many brain regions makes it particularly challenging to evaluate tissue accessibility. PET imaging, with its ability to provide real‐time imaging of the spatial distribution, concentration and kinetics of radiolabelled α7 nAChR ligands, allows us to assess whether a compound can effectively reach these receptors [8]. This is especially important for radioligands designed to target α7 nAChRs, as ensuring adequate brain penetration and binding to α7 receptors is crucial for developing drugs that target this receptor [9]. The radiolabelled compound can then be evaluated for pharmacokinetics (PK) and distribution through microdosing or Phase 0 studies, where a trace amount of the radiolabelled compound is administered without inducing any pharmacological effect. However, this approach presents inherent challenges, such as the need to incorporate the isotope into the drug molecule late in the synthesis process to avoid altering its pharmacological properties. Overcoming these challenges is critical for ensuring that the radiolabelled drug candidate can be used effectively in both animal and human studies for PK and distribution assessments [10]. These studies help determine if drug candidates can achieve sufficient tissue exposure to α7 nAChRs in preclinical and clinical settings.

4. Measuring Target Engagement Through PET Imaging

Once it is confirmed that the radioligand or drug candidate can reach α7 nAChRs in the brain, the next crucial step is to evaluate target engagement—whether the compound is binding effectively to the receptor. PET imaging plays a vital role in visualizing in vivo interactions between the drug and α7 nAChRs, providing key insights for optimizing dosage in clinical trials [11]. This is achieved through target or receptor occupancy studies, which assess the proportion of receptors occupied by the drug, offering an essential understanding of how target engagement correlates with downstream pharmacological effects. Given the challenges posed by the low density of α7 nAChRs in the brain, PET imaging using competition binding studies is particularly valuable. These studies allow researchers to quantify α7 nAChR occupancy and determine the appropriate dose required to achieve effective target engagement. Radioligands like ¹¹C‐NS14492 and ¹⁸F‐ASEM, which exhibit specific binding (SB) to α7 nAChRs, are instrumental in these occupancy studies. They offer the advantage of testing multiple drug candidates with the same radioligand, avoiding the need to radiolabel each compound individually.

Typically, occupancy is measured by performing two PET scans: a baseline scan that assesses selective radioligand uptake and a challenge scan after drug administration. The reduction in radioligand uptake between these scans reflects the proportion of α7 nAChRs occupied by the drug.

5. PET Imaging to Assess Downstream Pharmacology

The final pillar of survival—downstream pharmacology—focuses on understanding how α7 nAChR–targeted drugs influence molecular and physiological processes beyond target engagement. PET imaging can offer critical insights into the pharmacodynamic (PD) effects of drugs on α7 nAChR–mediated signalling pathways. For example, α7 nAChRs are known to modulate key processes like neuroinflammation, cognitive function and neurotransmitter release, making it essential to understand how drugs targeting these receptors impact these pathways. Such insights are crucial for developing effective treatments for CNS diseases like ad and schizophrenia.

PET imaging has already provided key insights into downstream effects in related neurotransmitter systems, particularly in the dopamine system for antipsychotic drug development [12]. In these studies, PET radioligands have been instrumental in studying dopamine synthesis capacity, baseline D2 and D3 receptor binding potential (BP), and dopamine release in response to pharmacological interventions. Similarly, as more selective α7 nAChR radioligands become available, PET imaging could be used to track changes in α7 nAChR–mediated signalling pathways and link them to broader therapeutic outcomes. Beyond neurotransmitter systems, PET imaging is applied to investigate molecular‐level downstream events, including signal transduction pathways [13], gene expression [14] and changes in protein function [15]. Using these capabilities, PET imaging can help elucidate how α7 nAChR–targeted drugs alter complex molecular processes, providing a comprehensive view of their PD impact on both CNS and non‐CNS systems.

6. PET Imaging of the α7 nAChR

PET radioligands targeting α7 nAChRs have been developed to study the distribution, density and occupancy of these receptors in vivo, providing a valuable tool for investigating the development and progression of CNS diseases linked to α7 nAChRs [16] (Table 1). However, the process has been challenging due to the receptor's low density in the brain [33], with human in vivo estimates ranging between 0.67 and 0.82 nM as measured by PET imaging using ¹⁸F‐ASEM [34]. For comparison, this density is significantly lower than that of other CNS receptors, such as dopamine D2 and serotonin 5‐HT2A receptors, which often exhibit densities in the high nanomolar range [35, 36]. This underscores the challenges in imaging α7 nAChRs, necessitating radioligands with exceptionally high binding affinities and selectivity to ensure sufficient signal detection in vivo. Krohn and Vera [37] highlight this as a critical consideration in the design of receptor‐binding radiotracers, emphasizing the need to match ligand properties with the specific density and distribution characteristics of the target receptor. In addition to human studies, rodent models have provided insights into the distribution of α7 nAChRs [38]. Autoradiography studies using ¹²⁵I‐α‐bungarotoxin have shown that α7 nAChRs in rat brains are predominantly localized in the hippocampus, with additional significant binding observed in the inferior colliculus, frontal cortex and superior colliculus. The receptor density follows the order: hippocampus > inferior colliculus > frontal cortex > superior colliculus > subiculum > thalamus > striatum > cerebellum. Such rodent studies complement human imaging data by providing a foundation for understanding receptor distribution and preclinical evaluation of radioligands.

TABLE 1.

Radioligands targeting the α7 nAChR.

Name (type)	Affinity	Animals tested in	Study highlights	Reference
11C‐2 (A)	n.s.	Rats	Reasonable uptake in several brain regions	[17]
11C‐3 (n.s.)	K d = 0.54 nM	Mice	High binding affinity, no in vivo studies conducted	[18]
11C‐4 (n.s.)	K d = 5.8 nM	Mice	High binding affinity, no in vivo studies conducted	[18]
18F‐6 (A)	K i = 1.3 nM	Baboons	Poor signal in the baboon brain	[19]
18F‐7 (A)	K i = 18 nM	Rats	Showed low and homogeneous distribution	[20]
11C‐A‐582941 (A)	K i = 10.8–17 nM	Mice, monkeys	Good BBB penetration but lacked sufficient regional specificity	[21]
11C‐A‐752274 (A)	K d = 0.092 nM	Mice, baboons	Ultra‐high binding affinity but low brain uptake	[22]
11C‐A‐833834 (A)	K d = 1.53 nM	Mice, baboons	High binding affinity but low brain uptake	[22]
11C‐A‐844606 (A)	IC50 = 11 nM (rat)	Mice, monkeys	Good BBB penetration but lacked sufficient regional specificity	[21]
18F‐ASEM (AN)	K i = 0.37 nM	Mice, baboons, pigs, humans	Second human in vivo PET study. Good brain uptake and regional binding. Widely used	[23]
18F‐AZ11637326 (A)	K d = 0.2 nM	Mice, monkeys	Limited brain uptake	[24]
11C‐CHIBA‐1001 (PA)	K d = 120–180 nM	Monkeys, humans	First α7 nAChR–specific radioligand tested in humans with heterogeneous brain uptake	[25]
18F‐DBT10 (AN)	K i = 1.32 nM	Mice	Similar uptake and binding as 18F‐ASEM	[23]
11C‐GTS‐21 (PA)	Low (n.s.)	Baboons, mice	First 11C‐labelled PET radioligand tested in vivo	[26]
11C‐(R)‐MeQAA (PA)	K i = 41 nM	Mice, monkeys, humans	Good brain uptake, useful in ad and schizophrenia studies	[27]
18F‐NS10743 (A)	K d = 8.99 nM	Mice, pigs	Good BBB permeability, but limited specificity	[28]
18F‐NS14490 (A)	K i = 2.5 nM	Mice, pigs	Limited brain uptake	[29]
11C‐NS14492 (PA)	K i = 2.2 nM	Pigs	Dose‐dependent signal blocking. Good BBB penetration, promising for α7 nAChR imaging	[30]
76Br‐SSR180711 (PA)	K i = 14–22 nM	Monkeys	Good specificity in competition binding studies	[31]
18F‐YLF‐DW (A)	K i = 2.98 nM	Mice	Promising brain uptake, used for atherosclerotic plaques identification	[32]

Abbreviations: Type: A = agonist, AN = antagonist, n.s. = not specified, PA = partial agonist.

For effective PET imaging, a radioligand must have high specificity, low nanomolar or picomolar binding affinity, good brain penetration and suitable pharmacokinetic properties. The following section reviews current radioligands for α7 nAChRs, focusing on their strengths and limitations.

¹¹C‐GTS‐21, a partial agonist for the α7 nAChR, was the first PET radioligand to be evaluated in vivo (Figure 2). It was radiolabelled at two distinct positions, along with two metabolites, for pharmacokinetic PET studies in baboons and mice. However, it demonstrated only limited specificity [26].

FIGURE 2.

The first in vivo PET images of α7 nAChR in baboons using three ¹¹C‐labelled variants of GTS‐21. Source: Reprinted from Kim et al. [26], doi: 10.1016/j.nucmedbio.2007.04.005, 2007, Elsevier Inc.

SSR180711 demonstrated strong binding affinity for rat and human α7 nAChRs and was radiolabelled with ⁷⁶Br and ¹¹C, producing ⁷⁶Br‐SSR180711 and ¹¹C‐SSR180711, respectively. Additionally, an analogue of ⁷⁶Br‐SSR180711 was developed by replacing ⁷⁶Br with ¹¹CH₃, resulting in ¹¹C‐CHIBA‐1001 [31]. Both ⁷⁶Br‐SSR180711 and ¹¹C‐CHIBA‐1001 were tested in rhesus monkeys, revealing a heterogeneous distribution pattern, with good brain region–specific uptake. Specificity was confirmed through competition binding studies, which led to ¹¹C‐CHIBA‐1001 becoming the first α7 nAChR–specific radioligand to be tested in humans in vivo [25] (Figure 3).

FIGURE 3.

The first in vivo PET images of α7 nAChR in humans using 11C‐CHIBA‐1001. Top panel: corresponding MRI slices. Middle panel: static images from 0 to 90 min post ¹¹C‐CHIBA‐1001 injection, displayed as SUV. Bottom panel: total distribution volume of 11C‐CHIBA‐1001 based on Logan graphical analysis (30‐ to 90‐min data). Source: Figure reprinted with permission from Toyohara et al. [25], doi: 10.1007/s12149‐009‐0240‐x, 2009, The Japanese Society of Nuclear Medicine.

The study demonstrated a heterogeneous pattern of brain uptake, with the highest levels observed in the thalamus. However, in humans, radioligand uptake in the cerebellum was comparable to that in the cerebral cortex, which differed from findings in monkeys. This discrepancy may be attributed to low receptor affinity and as a result, no further development of the radioligand has been pursued [39].

Three 1,4‐diazabicyclo[3.2.2]nonane derivatives, specific to α7 nAChRs, were radiolabelled as potential PET radioligands: (1) ¹⁸F‐NS10743, which demonstrated good binding affinity for α7 nAChRs. Ex vivo studies in mice showed good BBB permeability and target specificity [28]. However, subsequent in vivo PET studies in pigs indicated only modest specificity, as seen by a low reduction in SB in competition binding studies [40]. (2) ¹¹C‐NS14492, a selective α7 nAChR partial agonist, was evaluated using in vivo PET imaging in pigs. The radioligand showed good BBB penetration, with high binding in the thalamus and cerebral cortex, moderate binding in the striatum, and low cerebellar binding, consistent with the known distribution of α7 nAChRs in the human brain. Selectivity was confirmed through dose‐dependent signal blocking with predosing of cold NS14492 and SSR180711 [30], and further validation through a tritiated version was done [41]. Recently, ¹¹C‐NS14492 was used to directly compare the target engagement of two α7 nAChR–specific compounds, the previous drug candidates encenicline (EVP‐6124) and bradanicline (TC‐5619) [42]. Collectively, these results indicate that ¹¹C‐NS14492 is a promising radioligand for α7 nAChRs brain imaging. (3) ¹⁸F‐NS14490 was developed as a radioligand with strong binding affinity and selectivity; however, PET studies in both mice and pigs demonstrated limited brain uptake [29].

¹⁸F‐ASEM and its isomer, ¹⁸F‐DBT10, are two potent α7 nAChR antagonists with their high binding affinity and selectivity. In biodistribution studies conducted in mice, ¹⁸F‐ASEM showed greater brain uptake compared to ¹⁸F‐DBT10 [43]. Due to their structural similarities, further investigation focused on ¹⁸F‐ASEM. These studies revealed heterogeneous brain binding, with the highest uptake in the hippocampus and frontal cortex, intermediate levels in the striatum, and low uptake in the cerebellum, aligning with known α7 nAChR distribution in the mouse brain. Similar findings, including dose‐dependent blocking in in vivo competition studies, were replicated in baboons [44] and pigs [45]. The successful animal studies paved the way for the first in vivo PET study in humans using ¹⁸F‐ASEM, making it only the second radioligand tested in humans for α7 nAChRs [23]. In this study, ¹⁸F‐ASEM displayed good brain uptake with regional binding patterns that mirrored postmortem human and non‐human primate data, showing high levels in the parietal cortex, putamen, thalamus, temporal lobes, cingulate, frontal lobes and hippocampus. This human study spurred a series of further investigations: Coughlin et al. [46] studied the potential correlation between α7 nAChR distribution and aging in 25 healthy volunteers aged 21–86. They observed that VT's across six brain regions, including the striatum and five cortical areas, negatively correlated with age. Coughlin et al. [47] used ¹⁸F‐ASEM to examine α7 nAChR distribution in 11 individuals with recent‐onset psychosis compared to 15 healthy controls, finding reduced binding in the hippocampus among the patient group. In another study, ¹⁸F‐ASEM was used to investigate α7 nAChR distribution in 14 participants with mild cognitive impairment compared to 17 healthy controls, revealing elevated binding across all brain regions in the cognitively impaired group, suggesting increased receptor density [48]. Several recent studies are also noteworthy: Vetel et al. [49] explored the evolution of α7 nAChR expression in an early‐stage Parkinson's disease rat model using in vivo PET and identified a transient, early increase in receptor expression in the lesioned striatum and substantia nigra. Yang et al. [50] investigated α7 nAChR expression in the vasculature using two animal models of atherosclerosis, demonstrating that ¹⁸F‐ASEM could effectively locate atherosclerotic plaques and assess their vulnerability to rupture. Kim et al. [51] highlighted the potential of α7 nAChR imaging as a non‐invasive diagnostic tool for peripheral nervous system disorders. Nag et al. [52] applied in silico modelling to design ASEM analogues with improved radioligand properties and tested six leading compounds using in vitro autoradiography in postmortem human tissue and in vivo PET imaging in non‐human primates. Lastly, two recent abstracts reported increased α7 nAChR availability in the brains of older, cognitively normal individuals [53] and reduced hippocampal α7 nAChR levels in patients with recent‐onset psychosis [54].

¹¹C‐(R)‐MeQAA was developed with reasonable binding affinity and biodistribution properties. In vivo receptor blocking studies in mice demonstrated high initial brain uptake, with a heterogeneous distribution characterized by strong binding in the hippocampus and low binding in the cerebellum. Pretreatment with the α7 nAChR antagonist MLA significantly blocked signals in the hippocampus. Subsequent PET imaging studies in rhesus monkeys revealed regional brain uptake, showing high levels in the thalamus, moderate levels in the cerebral cortex and low levels in the cerebellum [27]. In a clinical study involving 20 patients with ad and 10 healthy, age‐matched controls, ¹¹C‐(R)‐MeQAA was assessed alongside Aβ deposition using ¹¹C‐Pittsburgh compound B [55]. The results demonstrated significantly reduced ¹¹C‐(R)‐MeQAA binding in the temporal and prefrontal cholinergic projection regions of ad patients, with the binding levels correlating significantly with memory function scores. Additionally, a pilot study in patients with schizophrenia revealed significantly lower ¹¹C‐(R)‐MeQAA BPND levels in the middle frontal cortex, with a trend towards reduced levels in the temporal and parietal cortices. No differences were observed in the superior frontal cortex [56]. No further development of the radioligand has been reported.

In the interest of conciseness, the following nine α7 nAChR radioligands deserve brief mention, despite their failure due to various issues: (1) ¹¹C‐2 showed no specific accumulation and low SB, [17]; (2) ¹¹C‐3 and ¹¹C‐4 demonstrated low brain uptake with homogeneous distribution [18]; (3) 18F‐6 showed a weak binding signal [19]; (4) ¹⁸F‐7 had low, homogeneous distribution with poor SB [20]; (5) ¹⁸F‐AZ11637326 showed limited brain uptake and low SB [24]; (6) ¹¹C‐A‐582941 and (7) ¹¹C‐A‐844606 both crossed the BBB in mice and monkeys but lacked sufficient regional selectivity and specificity [21]; and (8) ¹¹C‐A‐752274 and (9) ¹¹C‐A‐833834, despite high binding affinity, displayed low brain uptake [22]. Finally, Wang et al. [32] developed ¹⁸F‐YLF‐DW, which demonstrated promising brain uptake in initial mouse studies. It was later applied to identify vulnerable atherosclerotic plaques in the carotid arteries [57]. This example illustrates that whole‐body PET targeting α7 nAChRs in the periphery could complement CNS‐focused studies and help identify new therapeutic targets.

7. Comparative In Vivo Properties of Key Radioligands

To further evaluate the strengths and limitations of key radioligands, a comparative analysis of their in vivo imaging properties is presented in Table 2.

• ¹¹ C‐NS14492 shows high BP (5–9 mL/cm³) in the cortex and thalamus, with robust receptor occupancy (61%–81%) confirmed through dose‐dependent blocking studies. However, its rapid metabolism and lack of clinical validation limit its applicability to preclinical settings [30].

• ¹⁸ F‐ASEM stands out for its high reproducibility (variability < 7%) and broad validation in humans, with BP ranging from 0.7 to 3.0 in α7‐enriched regions like the hippocampus and frontal cortex. While its occupancy range (17%–49%) is slightly lower than preclinical tracers, it remains a gold standard for human studies [23].

• ¹¹ C‐(R)‐MeQAA, although limited by moderate specificity and slower kinetics, provides valuable insights into disease mechanisms, particularly Alzheimer's disease, where reduced binding correlates with cognitive deficits (BP 0.6–1.5 in the hippocampus and cortical regions) [55].

TABLE 2.

Radioligand in vivo comparison.

Radioligand	Binding potential (BPND) (mL/cm3)	Regions with high uptake	Receptor occupancy (context‐specific)	Key observations	Key drawbacks
11C‐NS14492	5–9	Cortex, thalamus	61%–81% (pigs, SSR180711 or unlabelled NS14492, dose‐dependent)	Good specificity, robust occupancy	Fast metabolism limits its use in humans; no extensive clinical validation
18F‐ASEM	0.7–3.0	Hippocampus, frontal cortex	17%–49% (humans, DMXB‐A 150 mg, 40 min prior to scan)	High reproducibility, broad validation in human studies	Lower occupancy range compared to preclinical tracers; slightly limited specificity
11C‐(R)‐MeQAA	0.6–1.5	Hippocampus, cortical regions	N/A (no explicit receptor occupancy study reported)	Moderate affinity, reduced binding in ad correlates with cognitive scores.	Moderate specificity and slower pharmacokinetics limit broader applicability.

Note: Receptor occupancy values are context‐specific and influenced by experimental conditions, including species, dose of the blocking agent and timing relative to the PET scan.

These radiotracers collectively highlight the diversity of tools available for imaging α7 nAChRs, each suited to specific research contexts and applications.

8. Conclusion

The development of PET radioligands targeting α7 nAChRs has encountered significant hurdles, particularly due to the low density of these receptors in the brain, challenges in achieving high specificity and the difficulty of ensuring adequate brain penetration. Despite these challenges, several promising radioligands, such as ¹¹C‐(R)‐MeQAA, ¹¹C‐NS14492 and ¹⁸F‐ASEM, have shown potential for studying α7 nAChR distribution, density and occupancy in vivo. These radioligands offer valuable tools for understanding the role of α7 nAChRs in CNS diseases, such as Alzheimer's disease, schizophrenia and cognitive decline.

Comparative evaluations highlight the unique strengths and limitations of these radioligands. ¹¹C‐NS14492 demonstrates high BP and robust receptor occupancy in preclinical models but is limited by rapid metabolism and a lack of clinical validation. ¹⁸F‐ASEM, validated across species and disease contexts, is a benchmark radioligand known for its reproducibility and specificity. While ¹¹C‐(R)‐MeQAA is constrained by slower PK and moderate specificity, it provides critical insights into disease mechanisms, particularly its correlation with cognitive deficits in Alzheimer's disease. Rather than identifying a single ‘best’ radiotracer, this review highlights the need for context‐driven selection based on experimental goals and research applications.

Looking ahead, the future of PET imaging for α7 nAChRs remains promising. Continued innovation in radioligand development and validation, including the design of more selective and brain‐penetrant compounds, will be crucial to unlocking the full potential of α7 nAChR–targeted imaging. Moreover, the emerging applications of whole‐body PET imaging, particularly in identifying peripheral targets and novel therapeutic avenues, underscore the relevance of PET in both CNS and non‐CNS disease research. As new radioligands are developed and refined, PET imaging is poised to play an increasingly important role in the diagnosis, treatment and management of α7 nAChR–related disorders.

Conflicts of Interest

The author declares no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.