In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

Abstract

Positron emission tomography (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent ¹⁸F-labeled PDE10A radioligands (¹⁸F-TZ19106B and ¹⁸F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of ¹⁸F-TZ19106B and ¹⁸F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). ¹⁸F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than ¹⁸F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BP_ND) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of ¹⁸F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of ¹⁸F-TZ19106B binding to varying number of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of ¹⁸F-TZ19106B. Our results indicate that ¹⁸F-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to determine target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies.

Keywords: PET radioligands; Phosphodiesterase 10A; brain imaging; in vivo characterization; nonhuman primates; psychotic disorders.

Figure 1

Chemical structures of leading PDE10A radioligands.

Figure 2

Time–activity curves (TACs) of microPET in NHP brains using two PDE10A radioligands ¹⁸F-TZ19106B, and ¹⁸F-TZ8110. (a) ¹⁸F-TZ19106B TACs in NHP striatum and cerebellum using averaged SUVs (n = 2 scans), striatum uptake reached the max SUV value (∼1.76) at 90–100 min postinjection and decreased gradually; (b) ¹⁸F-TZ8110 TACs in NHP striatum and cerebellum (n = 1 scan), the peak (SUV value ∼ 0.58) appeared at 30–40 min postinjection and declined relatively rapidly. Note: To minimize noise signal in the presentation, data in TAC graphics have been smoothed by “LOWESS” using GraphPad Prism 6.0 (GraphPad Software, Inc., San Diego, CA), while tracer kinetic analysis was based on original data without smoothing.

Figure 3

Correlation between BP_ND-LoganREF and BP_ND-RTM for ¹⁸F-TZ19106B and ¹⁸F-TZ8110 in NHP striatum. n = 5 scans in 3 NHPs for ¹⁸F-TZ19106B (a), n = 6 scans in 3 NHPs for ¹⁸F-TZ8110 (b). Data from 0 to 120 min post-tracer injection were used for BP_ND estimates. BP_ND-LoganREF values of both tracers strongly correlated with BP_ND-RTM values.

Figure 4

Representative ¹⁸F-TZ19106B microPET images of NHP brain. High striatum uptake at baseline was blocked by pretreatments with 1.0 or 2.0 mg/kg MP-10, a specific PDE10A inhibitor. In contrast, pretreatment with (−)-eticlopride even increased the striatal uptake of ¹⁸F-TZ19106B. All PET images are summed from 0 to 120 min.

Figure 5

Displacement study of ¹⁸F-TZ19106B in NHP brain. The striatal uptake of 18F-TZ19106B significantly decreased after i.v. injection of MP-10 at 40 min post tracer injection (purple solid circles), while the tracer uptake in the cerebellum was not impacted by the MP-10 injection (purple open circles).

Figure 6

Simplified circuitry cartoon showing the interaction between PDE10A pathway and dopaminergic signaling in medium spiny neurons (MSNs) of striatum. Intercellular cAMP levels in MSNs is modulated by adenylate cyclase and PDE10A. Adenylate cyclase, which catalyzes the conversion of ATP to cAMP, is activated by D1 signaling and suppressed by D2 signaling. Concordantly, D2 inhibition induced by (−)-eticlopride removes the suppression of adenylate cyclase, resulting in increased cAMP levels, which lead to compensatory upregulation of PDE10A to hydrolyze overexpressed cAMP.