Radiosynthesis and biological evaluation of the new PDE10A radioligand [¹⁸F]AQ28A

Abstract

Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[ F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([ F]AQ28A). [ F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[ F]F-K -carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [ F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol ) for further evaluation. Initially, we investigated the binding of [ F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [ F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [ F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

“…Consequently, further development of appropriate PDE10A radioligands in our group was based on an alternative structural approach using 1-arylimidazo[1,5- a ]quinoxaline 46 (Figure 9) as lead compound [169]. Out of a small library of 1- and 8-(2′-fluoro)pyridine-substituted derivatives of 46 [170,171], compound 47 (AQ28A, Figure 9) showed high potency as well as best selectivity towards PDE10A (IC 50 = 2.95 nM and > 1000 nM for all other PDEs [171]) and has been selected for 18 F-labeling [170,172,173].…”

“…[ 18 F] 47 has been prepared initially by direct nucleophilic halogen exchange using the related bromo precursor and the K + /[ 18 F]F − /K 2.2.2 -carbonate complex in dimethyl sulfoxide [170,173]. To increase the radiochemical yield of [ 18 F] 47 , an optimized nucleophilic aromatic radiosynthesis procedure starting from the corresponding nitro precursor has been developed [172,173] (Scheme 13).…”

“…[ 18 F] 47 has been prepared initially by direct nucleophilic halogen exchange using the related bromo precursor and the K + /[ 18 F]F − /K 2.2.2 -carbonate complex in dimethyl sulfoxide [170,173]. To increase the radiochemical yield of [ 18 F] 47 , an optimized nucleophilic aromatic radiosynthesis procedure starting from the corresponding nitro precursor has been developed [172,173] (Scheme 13). In vitro autoradiography on mouse, rat and pig brain slices displayed region-specific binding of [ 18 F] 47 [172,173], which corresponds to the known PDE10A distribution pattern in brain of various mammalian species [130,131] and could also be detected by ex vivo autoradiographic studies in mouse brain at 30 min post injection.…”

“…To increase the radiochemical yield of [ 18 F] 47 , an optimized nucleophilic aromatic radiosynthesis procedure starting from the corresponding nitro precursor has been developed [172,173] (Scheme 13). In vitro autoradiography on mouse, rat and pig brain slices displayed region-specific binding of [ 18 F] 47 [172,173], which corresponds to the known PDE10A distribution pattern in brain of various mammalian species [130,131] and could also be detected by ex vivo autoradiographic studies in mouse brain at 30 min post injection. In microPET imaging studies in mice, a high initial brain uptake has been observed (SUV = 1.8 at 3 min p.i.)…”

“…Additionally, a striatum-to-cerebellum ratio of 1.4 at 30 min post injection and a 60% reduced striatal uptake after pre-treatment with 22 indicate specific binding of [ 18 F] 47 in vivo . Metabolism studies in mice revealed 35%–57% of intact [ 18 F] 47 in plasma and 71% in brain, respectively, at 30 min post injection [173]. Formation of two brain penetrating radiometabolites has been observed which are slightly more polar than [ 18 F] 47 and thus might result from metabolic hydroxylation or O -demethylation [169].…”