[3H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement.
Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC50value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain.
Biology and Chemistry, Bristol-Myers Squibb Biocon Research Center, Bangalore, India.
Justin V
JV
Louis
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Yifeng
Y
Lu
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Rick
R
Pieschl
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Yung
Y
Tian
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Yang
Y
Hong
Biology and Chemistry, Bristol-Myers Squibb Biocon Research Center, Bangalore, India.
Kumaran
K
Dandapani
Biology and Chemistry, Bristol-Myers Squibb Biocon Research Center, Bangalore, India.
Sreenivasulu
S
Naidu
Biology and Chemistry, Bristol-Myers Squibb Biocon Research Center, Bangalore, India.
Reeba K
RK
Vikramadithyan
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Carolyn
C
Dzierba
Biology and Chemistry, Bristol-Myers Squibb Biocon Research Center, Bangalore, India.
Sarat Kumar
SK
Sarvasiddhi
Biology and Chemistry, Bristol-Myers Squibb Biocon Research Center, Bangalore, India.
Susheel J
SJ
Nara
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Joanne
J
Bronson
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
John E
JE
Macor
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Charlie
C
Albright
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
Walter
W
Kostich
Neuroscience Biology, Neuroscience Chemistry, Radiochemistry and Veterinary Science, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA. Electronic address: yuwenli@yahoo.com.
Yu-Wen
YW
Li
D000588:Amines / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D007839:Functional Laterality; D000077206:Gabapentin; D000882:Haplorhini; D006930:Hyperalgesia / Q000209:etiology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D013119:Spinal Cord Injuries / Q000150:complications*; D014316:Tritium / Q000493:pharmacokinetics; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics
D000588:Amines; C000622194:BMT-046091; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D014316:Tritium; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D017346:Protein Serine-Threonine Kinases
Adaptor-associated kinase 1; Central nervous system; Dorsal horn; Neuropathic pain; Non-human primate; Occupancy; Radioligand binding; Rodent