Synthesis and organ distribution of [18F]fluoro-Org 6141 in the rat: a potential glucocorticoid receptor ligand for positron emission tomography.
For the synthesis of [18F]Fluoro-Org 6141 via a nucleophilic substitution reaction with 18F-, the tosyl group was chosen as the leaving group because of its stability and excellent leaving group ability. The biodistribution of the high affinity and moderate lipophilicity (log P = 2.66, calculated value) ligand [18F]Fluoro-Org 6141 (specific activity 8.2 to 37 TBq/mmol, yield 10% at EOB) was examined in sham adrenalectomized (sADX) and adrenalectomized (ADX) male Wistar rats. Two days after ADX or sADX, the animals were anesthetized and 0.37 to 1.85 MBq of [18F]Fluoro-Org 6141 was administered intravenously. Kinetics of 18F activity uptake were monitored for 3 h using a stationary double-headed positron emission tomography (PET) camera, and the biodistribution was assessed by ex vivo determination of radioactivity in several tissues and different brain areas. One hour after injection of the radioligand, the bladder, kidney, liver, trachea, and bone of sADX animals contained more concentration on a wet weight basis than blood. Three hours post injection, radioactivity was retained in bladder, trachea, and bone. The accumulation of radioactivity in brain corresponded to the concentration of activity in the blood within the first hours after injection. ADX animals showed a higher uptake of 18F activity in spleen, testes, and brain areas (hippocampus and brainstem) but a lower uptake in bone than sADX rats. PET scans suggested that 18F activity uptake in the brain had not yet reached a maximum at this interval. Although [18F]Fluoro-Org 6141 is not useful for PET studies of glucocorticoid receptors (GRs), the results obtained with this compound indicate a synthetic strategy suitable for the synthesis of high-affinity radioligands for GRs.
PET Center and Groningen Center for Catalysis and Synthesis, Groningen, The Netherlands.
G M
GM
Visser
H J
HJ
Krugers
G
G
Luurtsema
A
A
van Waarde
P H
PH
Elsinga
E R
ER
deKloet
M B
MB
Groen
B
B
Bohus
K G
KG
Go
A M
AM
Paans
D000818:Animals; D004355:Drug Stability; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008297:Male; D009653:Norprogesterones / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000032:analysis*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D005462:Fluorine Radioisotopes; D008024:Ligands; D009653:Norprogesterones; C097716:Org 6141; D011965:Receptors, Glucocorticoid