Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

Abstract

The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

18F-Labeled PET Tracers Specific for Adenosine A2A Receptor: Design, Synthesis, and Biological Evaluation

“…[ 18 F]­3 has a high affinity for A 2A R in vitro and can effectively penetrate the blood–brain barrier, but it also exhibits severe off-target in the brain and defluorination. Lai et al also modified the structure of high-affinity A 2A R therapeutics, such as tozadenant and PPY, aimed at synthesizing potential tracers with a stronger affinity for A 2A R receptors. , However, PET imaging revealed that such compounds had serious off-target imaging in the brain. , The possible explanation for off-target phenomenon may be that other targets have a higher affinity for these tracers than A 2A R or other targets have a lower affinity for tracers than A 2A R, but their content is much higher than A 2A R. From the experience of these failures, radiopharmaceuticals can efficiently validate the targeting specificity and selectivity of therapeutic drugs to improve the progress of drug research.…”

“…37,38 However, PET imaging revealed that such compounds had serious off-target imaging in the brain. 37,38 The possible explanation for off-target phenomenon may be that other targets have a higher affinity for these tracers than A 2A R or other targets have a lower affinity for tracers than A 2A R, but their content is much higher than A 2A R. From the experience of these failures, radiopharmaceuticals can efficiently validate the targeting specificity and selectivity of therapeutic drugs to improve the progress of drug research.…”

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

“…Among the nine compounds, only the F-substituted 6-and 7-azaindoles bound σ 1 receptors with an affinity low enough (K i values > 500 nM) to exclude confounding binding in imaging studies performed at low-to sub-nanomolar concentration of the radiotracer. To finally select the best derivative for radiofluorination, we calculated the σ 2 :σ 1 selectivity values and identified RM273 (41) as the most suitable one with a ratio of about 400.…”

“…For this purpose, the boronic acid pinacol ester precursor 45 was synthesized in one step from the corresponding bromo-derivative 44 via the Miyaura borylation reaction in high yield (>85%) as shown in Scheme 2 [40]. As described previously [34,39] and based on our own work [41] on the coppermediated radiofluorination of aryl boronic acid pinacol esters, manual radiosynthesis of [ 18 F]RM273 (Scheme 2) was performed initially to check if the reaction conditions usually applied for this kind of radiofluorination (e.g., [ 18 F]TBAF system in DMA and tBuOH as solvents) would give reasonable yields for further translation to an automated radiosynthesis module. Radiochemical yields of about 50% (calculated from the crude reaction mixture, non-decay-corrected) were obtained using the pinalcol precursor 45 and Cu(OTf) 2 (py) 4 at a molar ratio of approximately 1:4, and no further optimization was carried out.…”

Receptors Involved in Mental Disorders and the Use of Clozapine, Chlorpromazine, Olanzapine, and Aripiprazole to Treat Mental Disorders

“…There is a notion that overstimulation of D2 receptors could be accountable for schizophrenia-positive symptoms. Scientists further found out that levodopa, a DA precursor, and amphetamine, a DA-releasing agent, worsened the symptoms of schizophrenia [1,4,5,[8][9][10][11][12][13][14][15][16]. Neuroimaging studies have revealed that schizophrenic patients display an escalated release of DA in the ventral striatum after amphetamine induction, indicating heightened sensitivity of their dopaminergic system when compared with a control group.…”