Synthesis and in vivo Evaluation of Fluorine‐18 and Iodine‐123 Pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A_2A Receptors

Abstract

Imaging agents that target adenosine type 2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson's disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A2A ligands, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine-18 or iodine-123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7-(2-(4-(4-(2-[(18) F]fluoroethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine ([(18) F]MNI-444) and 7-(2-(4-(2-fluoro-4-[(123) I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([(123) I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A2A receptors in brain.

Adenosine A2A receptor antagonists: from caffeine to selective non‐xanthines

“…[ 11 C]SCH442416 (structure not shown), an A 2A receptor antagonist, was used to establish the human brain receptor occupancy of a potential anti‐PD drug vipadenant (Figure 1, compound 14 ; Brooks et al, 2010). Single‐photon emission computerized tomography (SPECT) using an labelled A 2A receptor antagonist [ 123 I]MNI‐420, a pyrazolo[4,3‐ e ][1,2,4]triazolo[1,5‐ c ]pyrimidin‐5‐amine (Figure 1, compound 12), has also been reported (Vala et al, 2016). However, endogenous adenosine levels were unable to be determined using rat PET imaging using adenosine receptor antagonist tracers.…”

“…Thus, blockade of the A 2A receptor by caffeine or selective A 2A receptor antagonists provides benefit to humans and in animal models related to PD, AD, impairment from traumatic brain injury, ADHD, risk to develop stroke, depression, and suicidal behaviour (Cunha, 2016). pound 12), has also been reported (Vala et al, 2016). However, endogenous adenosine levels were unable to be determined using rat PET imaging using adenosine receptor antagonist tracers.…”

Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics

“…For example, use of a mild (AIBN/NBS promoted) route to the 8-substituted xanthine scaffold resulted in an improvement in yield from 22% to 56% for this key step (see experimental section) [ 29 ]. Compounds 4 and 5a were synthesized based on modified literature methods ( Scheme 1 ) [ 30 – 33 ], key intermediate 13 obtained from compound 7 via Vilsmeier-promoted halogenation and formylation, one-pot cascade condensation with 2-furoic acid hydrazine (9) and 2-hydroxyethyl hydrazine (11) , Dimroth rearrangement to effect triazole formation, and finally bromination with POCl 3 /ZnBr 2 . The piperazine components were prepared starting from either commercially available fragment 14 or fluorination/activation of the known mono- or ditosylated PEG chains (15 – 19) and subsequent coupling reaction with 1-(4-(4-hydroxyphenyl) piperazin-1-yl)ethan-1-one (20) and then deacetylation prior to the final coupling reaction with intermediate 13 to furnish 4 and the desired analogs 27 – 31 [ 30 , 34 ].…”

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

“…131 [ 18 F]MNI-444 radioligand has shown high uptake, rapid kinetics, and high target/nontarget ratios in the brain, consistent with A 2A receptor distribution. 131,132 Thus far, [ 18 F]MNI-444 has turned out to be a superior imaging tracer among all the 18 F PET radioligands for studying and mapping the A 2A R in the brain. 133 A list of all A 2A receptor PET radioligands is presented in Table 2.…”