In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

Abstract

PET of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiologic functions as well as disease states involving the serotonergic system. The goal of this study was to further develop and refine a series of 49-fluoroalkoxy-substituted, 18 F-radiolabeled SERT imaging agents. 2-(29-((Dimethylamino)methyl)-49-(4-18 F-fluorobutoxy)phenylthiol)-benzenamine (3) and 2-(29-((dimethylamino)methyl)-49-(5-18 Ffluoropentoxy)phenylthiol)benzenamine (4) were synthesized and evaluated along with 2 previously reported compounds of this series, 2-(29-((dimethylamino)methyl)-49-(2-18 F-fluoroethoxy)-phenylthiol)benzenamine (1) and 2-(29-((dimethylamino)methyl)-49-(3-18 F-fluoropropoxy)phenylthiol)benzenamine (2). Methods: The in vitro binding affinities of compounds 3 and 4 were determined in monoamine transporter-transfected LLC-PK 1 cell homogenates. In vivo localization of the respective 18 F-labeled compounds was evaluated by biodistribution studies in male Sprague-Dawley rats. Compound 3 was selected for further examination by autoradiographic and PET studies in rats. Results: The corresponding mesylate precursors of 3 and 4 were radiolabeled with 18 F within 75-90 min. Radiochemical yield was 6%235%, specific activity was 15-170 GBq/mmol, and radiochemical purity was greater than 97% (end of synthesis). The compounds showed subnanomolar binding affinities for SERT (inhibition constants, 0.51 and 0.76 nM, respectively), had brain uptake at 2 min of 1.25 and 0.68 percentage injected dose per gram, respectively, and possessed high target-to-nontarget (hypothalamus-to-cerebellum) ratios at 120 min after injection (6.51 and 5.70, respectively). Autoradiographic studies of 18 F-3 showed selective localization in SERT-rich brain regions. PET studies of 18 F-3 showed clear localization in the midbrain, thalamus, and striatum. Conclusion: This compound series was found to have potential for producing a suitable 18 F-radiolabeled PET radiotracer for SERT. Compound 4, the pentoxy derivative, had the lowest brain uptake and target-to-nontarget ratio. Compound 3, the butoxy derivative, had a lower target-to-nontarget ratio than compounds 1 (ethoxy derivative) and 2 (propoxy derivative). Compounds 1 and 2 both hold promise as SERT radioimaging agents, but because of cost limitations, only compound 2 will be evaluated in further studies.

11C and 18F PET radioligands for the serotonin transporter (SERT)

“…Compounds [ 18 F] 23 –[ 18 F] 31 were radiolabeled by 18 F − displacement of a mesylate group followed by reduction of the 2‐nitro group (Scheme ) . The fluoroalkyl ethers [ 18 F] 23 –[ 18 F] 26 were obtained in 6–35% rcy, >97% rcp, and SA of 15–170 GBq/µmol .…”

“…Compounds [ 18 F] 23 , [ 18 F] 24 , and [ 18 F] 27 –[ 18 F] 31 were initially evaluated by rat brain biodistribution studies that identified [ 18 F] 23 and [ 18 F] 24 as the most promising candidates on the basis of high brain uptake and fast washout . PET studies in rats further confirmed that [ 18 ] 23 and [ 18 ] 24 are the most promising of this series …”

Deuterium‐substituted 2‐(2′‐((dimethylamino)methyl)‐4′‐[18F](fluoropropoxy)phenylthio)benzenamine as a serotonin transporter imaging agent

“…Previously, [ 18 F]FPBM (Figure 3) was reported with having substitution on the phenyl ring B (compared with [ 18 F]4‐FADAM or [ 11 C]DASB) (Figure 3). [ 18 F]FPBM possesses high selective binding, high brain uptake (0.99% dose/g at 2 min post iv injection), and an excellent in vivo target‐to‐nontarget ratio (7.7 at 120 min post injection) . Labeling studies suggested that there is a tendency to produce a vinyl side product through an elimination reaction during the S N 2 substitution by the activated [ 18 F]fluoride ion .…”

In vivo studies of the SERT-selective [18F]FPBM and VMAT2-selective [18F]AV-133 radiotracers in a rat model of Parkinson's disease

“…Using the longer lived 18 F isotope ( t 1/2 = 110 min) compared to the shorter lived 11 C isotope ( t 1/2 = 20 min) would allow medical centers, lacking the necessary radiochemistry facilities for their own production of the radiotracer to have access to the radiotracer from off-site commercial sources. Recently, a new promising SERT radiotracer, [ 18 F]FPBM (Fig 1), has been shown to possess high affinity ( K i = 0.38 nM), good selectivity, high brain uptake (0.99 % dose/g at 2 min post-injection), and an excellent target to non-target ratio (7.7 at 120 min post-injection) through in vitro binding assays, in vivo biodistribution, ex vivo autoradiography, and PET imaging studies in normal rats [23-25]. This compound was also amenable to simple radiosynthesis with relatively good radiochemical yields, good specific activity, and high radiochemical purity [23-25].…”

“…Recently, a new promising SERT radiotracer, [ 18 F]FPBM (Fig 1), has been shown to possess high affinity ( K i = 0.38 nM), good selectivity, high brain uptake (0.99 % dose/g at 2 min post-injection), and an excellent target to non-target ratio (7.7 at 120 min post-injection) through in vitro binding assays, in vivo biodistribution, ex vivo autoradiography, and PET imaging studies in normal rats [23-25]. This compound was also amenable to simple radiosynthesis with relatively good radiochemical yields, good specific activity, and high radiochemical purity [23-25]. With these promising results, further studies were performed with [ 18 F]FPBM in a rat model of Parkinson’s disease induced by a 6-hydroxydopamine (6-OHDA) unilateral lesion of the nigrostriatal pathway.…”