PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

Abstract

Purpose: The α₇ nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α₇ nAChRs PET radioligands, [¹⁸F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([¹⁸F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [¹⁸F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([¹⁸F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [¹⁸F]ASEM in humans.

Methods: PET scans with high specific activity [¹⁸F]ASEM or [¹⁸F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [¹⁸F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [¹⁸F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [¹⁸F]ASEM distribution volume (V _T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V _T was assessed.

Results: In the rhesus monkey brain [¹⁸F]ASEM and [¹⁸F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [¹⁸F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [¹⁸F]ASEM V _T. [¹⁸F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [¹⁸F]ASEM V _T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V _T values ranging from 19.6 ± 2.5 mL/cm³ in cerebellum to 25.9 ± 2.9 mL/cm³ in thalamus. Test-retest variability of V _T was 11.7 ± 9.8%.

Conclusions: These results confirm [¹⁸F]ASEM as a suitable radiotracer for the imaging and quantification of α₇ nAChRs in humans.

Keywords: ASEM; Alpha7; Nicotine; Nicotinic Acetylcholine Receptor; PET.

Figure 1

Chemical structures of [¹⁸F]ASEM and [¹⁸F]DBT-10

Figure 2

Comparison of [¹⁸F]ASEM and [¹⁸F]DBT-10 in arterial plasma of nonhuman primates at baseline. A: Parent fractions. B: Arterial input functions, in SUV units.

Figure 3

Comparison of baseline [¹⁸F]ASEM (A) and [¹⁸F]DBT-10 (B) time-activity curves (open symbols) with the preferred 2TCM fit (solid lines). Values are expressed in SUV. C shows kinetic parameters for each radiotracer estimated with 2TCM. Values shown indicate mean ± standard deviation.

Figure 4

[¹⁸F]ASEM Kinetics in Humans. A shows the measured parent [¹⁸F]ASEM fractions in arterial plasma (n=6; error bars are standard deviations). B shows the parent [¹⁸F]ASEM input functions in SUV units (n=6; shaded area indicates ± 1 standard deviation). C shows representative [¹⁸F]ASEM time-activity curves in SUV units for four regions. Solid lines indicate fits with MA1 using t*=30 min.

Figure 5

Parametric images of [¹⁸F]ASEM V_T for a representative subject. Top row shows anatomical MRI, while middle and bottom rows show test and retest V_T images, respectively. Red lines in the coronal MRI slice indicate location of sagittal slices. Vertical red lines in sagittal MRI slices indicate location of coronal MRI slice, far right. V_T was estimated with MA1, t*=30 min with 5 mm Gaussian smoothing. The V_T scale, in units of mL/cm³, is shown on right.