A New Class of Fluorinated A_2A Adenosine Receptor Agonist with Application to Last‐Step Enzymatic [¹⁸F]Fluorination for PET Imaging

Abstract

The A adenosine receptor belongs to a family of G-coupled protein receptors that have been subjected to extensive investigation over the last few decades. Due to their prominent role in the biological functions of the heart, lungs, CNS and brain, they have become a target for the treatment of illnesses ranging from cancer immunotherapy to Parkinson's disease. The imaging of such receptors by using positron emission tomography (PET) has also been of interest, potentially providing a valuable tool for analysing and diagnosing various myocardial and neurodegenerative disorders, as well as offering support to drug discovery trials. Reported herein are the design, synthesis and evaluation of two new 5'-fluorodeoxy-adenosine (FDA)-based receptor agonists (FDA-PP1 and FDA-PP2), each substituted at the C-2 position with a terminally functionalised ethynyl unit. The structures enable a synthesis of F-labelled analogues by direct, last-step radiosynthesis from chlorinated precursors using the fluorinase enzyme (5'-fluoro-5'-deoxyadenosine synthase), which catalyses a transhalogenation reaction. This delivers a new class of A adenosine receptor agonist that can be directly radiolabelled for exploration in PET studies.

Enzymatic Fluorination of Biotin and Tetrazine Conjugates for Pretargeting Approaches to Positron Emission Tomography Imaging

“…With both 12 and 13 to hand, our attention turned to further assembly through Sonogashira cross‐coupling. This was accomplished by using an excess of 12 over 13 in the Pd 2 (dba) 3 ‐catalysed reaction. The ClDA‐PEG‐ester 14 was recovered in high purity after chromatography and C 18 cartridge purification.…”

In Vivo Positron Emission Tomography Imaging of Adenosine A2A Receptors

“…Shimada et al have identified that xanthine bearing the styryl group showed selective A 2A R antagonistic properties (Schiffmann et al, 1991), and KF17837, a ligand with superior selectivity and potent affinity for A 2A Rs, was optimized for the development A 2A R PET tracers (Seale et al, 1988). At present, several PET tracers were reported, such as [11C]TMSX ([11C]KF18446) (Ishiwata et al, 2000a;Ishiwata et al, 2003b) (Wang et al, 2000) and [18F]MDMPC (Lowe et al, 2017), and were investigated as promising PET agents (Ishiwata et al, 1996;Stone-Elander et al, 1997;Wang et al, 2000). In addition, [11C]TMSX (formally designated as [11C]KF18446) was selected for medical applications (Ishiwata et al, 2005).…”

Halogenating Enzymes for Active Agent Synthesis: First Steps Are Done and Many Have to Follow

“…Recently, different pre-targeting strategies have been developed for treatment and imaging of different diseases. Those include e.g., radiolabeling of the human A2A adenosine receptor [169], a prostate cancer-related membrane protein [170] or the combined application of biotin and tetrazine-conjugate with antibodies [171]. In all cases, it was shown that the fluorinase (FlA) accepts substrates with different moiety at C-2 of the adenine ring.…”