Design and Synthesis of 2-Amino-4-methylpyridine Analogues as Inhibitors for Inducible Nitric Oxide Synthase and in Vivo Evaluation of [¹⁸F]6-(2-Fluoropropyl)-4-methyl-pyridin-2-amine as a Potential PET Tracer for Inducible Nitric Oxide Synthase

Abstract

A series of position-6 substituted 2-amino-4-methylpyridine analogues was synthesized and compounds 9, 18, and 20 were identified as the inhibitors with the greatest potential to serve as PET tracers for imaging inducible nitric oxide synthase (iNOS). [ 18 F]9 was synthesized and evaluated in a mouse model of lipopolysaccharide (LPS)-induced iNOS activation. In vivo biodistribution studies of [ 18 F]9 indicate higher tracer uptake in the lungs of the LPS-treated mice when compared to control mice. Tracer uptake at 60 min post-injection was reduced in a blocking study using a known inhibitor of iNOS. The expression of iNOS was confirmed by Western blot analysis of lung samples from the LPS-treated mice. MicroPET studies also demonstrated accumulation of radiotracer in the lungs of the LPS-treated mice. Taken collectively, these data suggest that [ 18 F]9 shows favorable properties as a PET tracer to image iNOS activation with PET.

Antisense peptide nucleic acid-functionalized cationic nanocomplex for in vivo mRNA detection

“…RAW264.7 cells were seeded in a 96-well plate at a density of 2 Â 10 4 cells per well and cultured in 100 ml of complete medium. One day prior to transfection, cells were activated with LPS and IFN-g. Twenty-four hours later, the medium was replaced with 100 ml fresh culture medium containing complexes of PNA-YR 9 . ODN .…”

“…95%) were hybridized with equal amounts of the complementary ODN at 958C in 50 ml 0.1 M NaCl for 5 min. The 123 I-PNA-YR 9 . ODN hybrids were cooled at RT for 10 min and immediately followed by incubation with 500 ml cSCK (0.07 mg ml …”

“…The prominent role of iNOS in ALI has spurred efforts towards developing iNOS protein probes and inhibitors for diagnosis and therapy, respectively [5][6][7][8][9]. An alternative strategy is to develop probes and inhibitors for the iNOS mRNA transcript that can be readily targeted by complementarily base pairing with an antisense oligodeoxynucleotide (ODN) or analogue [10][11][12].…”

“…Herein, we report specific in vitro and in vivo targeting of iNOS mRNA with an antisense nanocomplex, 123 I-PNA anti YR 9 . ODN anti .…”

“…ODN anti . cSCK, formulated by electrostatic complexation of a cSCK and a radiolabelled antisense 123 I-PNA anti YR 9 . ODN anti hybrid (figure 1).…”