In Vitro Metabolic Stability and in Vivo Biodistribution of 3-Methyl-4-furoxancarbaldehyde Using PET Imaging in Rats

Abstract

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is currently difficult to treat using clinically available analgesics. Recent work suggests a progressive depletion of nitric oxide (NO) in nerve cells may be responsible for the pathobiology of PDN. The nitric oxide donor, 3-methyl-4-furoxancarbaldehyde (PRG150), has been shown to produce dose-dependent analgesia in a rat model of PDN. To gain insight into the mechanism of analgesia, methods to radiolabel PRG150 were developed to assess the in vivo biodistribution in rats. The furoxan ring was labeled with (13)N to follow any nitric oxide release and the 3-methyl substituent was labeled with (11)C to track the metabolite using PET imaging. The in vitro metabolic stability of PRG150 was assessed in rat liver microsomes and compared to in vivo metabolism of the synthesized radiotracers. PET images revealed a higher uptake of (13)N over (11)C radioactivity in the spinal cord. The differences in radioactive uptake could indicate that a NO release in the spinal cord and other components of the somatosensory nervous system may be responsible for the analgesic effects of PRG150 seen in the rat model of PDN.

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

“…[30] Recently,t he metabolic stabilitya nd biodistribution of PRG150 were investigated using the synthesis of 11 Cand 13 N-labeled furoxan 26 a.P ositron emission tomography (PET) images revealed ah igher uptake of the 13 Ni sotope over 11 Ci nt he spinal cord, which indicatesakey role of NO releasei nt he somatosensory nervouss ystem responsible for the analgesic effect of PRG150. [31] 3. Synthesis, NO-donor properties, and pharmacological activity of furoxan-based hybrids 3.1.…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[ 13 N]NO 2 − is also used to prepare 13 N‐labeled diazo and azido compounds via a diazonium intermediate. The ensuing 13 N‐labeled azido compounds could be further used in cyclization reactions to form [ 13 N]triazoles, [ 13 N]tetrazoles, and the furaxan analogue [ 13 N]PRG150 (Scheme C) . Other 13 N‐labeling agents, such as [ 13 N]N 2 and [ 13 N]N 2 O, were also reported …”

Chemie der Positronenemissionstomographie: Aktuelle Fortschritte bei 11C‐, 18F‐, 13N‐ und 15O‐Markierungsreaktionen

“…[ 13 N]NO 2 − wurde auch verwendet, um 13 N‐markierte Diazo‐ und Azidoverbindungen über ein Diazoniumintermediat zu erhalten. Die resultierenden 13 N‐markierten Azidoverbindungen können dann in Cyclisierungsreaktionen eingesetzt werden, um [ 13 N]Triazole, [ 13 N]Tetrazole und das Furaxananalogon [ 13 N]PRG150 zu bilden (Schema C) . Über weitere 13 N‐Markierungsagenzien wie [ 13 N]N 2 und [ 13 N]N 2 O wurde ebenfalls berichtet …”