Radiobrominated probe targeting activated p38α in inflammatory diseases

Objective p38α, a member of the mitogen-activated protein kinase superfamily, is activated by external stimuli, followed by nuclear translocation for the regulation of inflammatory responses at the transcriptional and translational levels in inflammatory diseases. Thus, activated p38α would be an ap...

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Bibliographic Details
Published in:Annals of nuclear medicine 2022-10, Vol.36 (10), p.845-852
Main Authors: Hashimoto, Tomoyuki, Kondo, Naoya, Makino, Akira, Kiyono, Yasushi, Temma, Takashi
Format: Article
Language:English
Subjects:
Animal models
Bioaccumulation
Blood
Bromine isotopes
Computed tomography
Emission analysis
Evaluation
External stimuli
Fluorine
Imaging
Inflammatory diseases
Intravenous administration
Iodine 125
Iodine 131
Iodine isotopes
Kinases
MAP kinase
Medical imaging
Medicine
Medicine & Public Health
Nuclear Medicine
Nuclear transport
Organotin
Original Article
Photon emission
Precursors
Protein kinase
Radiation therapy
Radioactivity
Radiochemistry
Radioisotopes
Radiology
Synthesis
Tetrahydro-2H-pyran
Tributyltin
Tributyltin compounds
Turpentine
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Summary:Objective p38α, a member of the mitogen-activated protein kinase superfamily, is activated by external stimuli, followed by nuclear translocation for the regulation of inflammatory responses at the transcriptional and translational levels in inflammatory diseases. Thus, activated p38α would be an appropriate target molecule for in vivo noninvasive imaging and targeted radionuclide therapy. For this purpose, we designed a radiobrominated compound, 6-(4-[ 77 Br]bromo-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([ 77 Br]4-BR), based on a potent p38α selective inhibitor, R1487, for use with single-photon emission computed tomography. We synthesized [ 77 Br]4-BR and evaluated its effectiveness as an activated p38α imaging probe compared with our previous radioiodinated probe (6-(2-fluoro-4-[ 125 I]iodophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([ 125 I]4-IR)) in a mouse inflammatory model. Methods We designed [ 77 Br]4-BR by replacing the radioiodine of [ 125 I]4-IR or the fluorine of R1487 with radiobromine at the 4-position of the phenoxy ring. We synthesized 4-BR via a four-step process. The inhibitory potency of 4-BR was measured using an ADP-Glo™ kinase assay system. Radiosynthesis of [ 77 Br]4-BR was performed via an organotin–radiobromine exchange reaction using the corresponding tributyltin precursor. Radioactivity biodistribution was evaluated in normal ddY mice and turpentine oil-induced inflammation model mice for 120 min after intravenous administration of [ 77 Br]4-BR. The temporal changes in radioactivity in blood fractions were compared between [ 77 Br]4-BR and [ 125 I]4-IR. Results 4-BR was synthesized at a total yield of 9.1% and showed a p38α inhibitory potency similar to that of 4-IR. [ 77 Br]4-BR was successfully obtained from a tributyltin precursor with high radiochemical yield (89.9%), purity (95.9%), and molar activity (2.0 TBq/µmol). [ 77 Br]4-BR showed accumulation of high radioactivity in the inflamed tissue (3.4% ± 0.9% ID/g, peaking at 15 min), rapid delivery throughout the body, and rapid blood clearance with approximately half of the blood radioactivity existing as an intact form at 60 min. Although the maximum radioactivity accumulation in inflamed tissue after [ 77 Br]4-BR administration was approximately half that of [ 125 I]4-IR because of its faster blood clearance and lower free fraction in the input function, the inflamed tissue-to-bl
ISSN:0914-7187
1864-6433
DOI:10.1007/s12149-022-01764-2