Pharmacological evaluation of [123I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS).
OBJECTIVE
The study aims to evaluate the iodinated imidazopyridine, N',N'-diethyl-6-Chloro-(4'-[(123)I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide ([(123)I]-CLINDE) as a tracer for the study of peripheral benzodiazepine binding sites (PBBS).


METHODS
In vitro studies were performed using membrane homogenates and sections from kidney, adrenals, and brain cortex of Sprague-Dawley (SD) rats and incubated with [(123)I]-CLINDE. For in vivo studies, the rats were injected with [(123)I]-CLINDE. In competition studies, PBBS-specific drugs PK11195 and Ro 5-4864 and the CBR specific drug Flumazenil were injected before the radiotracer.


RESULTS
In vitro binding studies in adrenal, kidney, and cortex mitochondrial membranes indicated that [(123)I]-CLINDE binds with high affinity to PBBS, K(d) = 12.6, 0.20, and 3.84 nM, respectively. The density of binding sites was 163, 5.3, and 0.34 pmol/mg protein, respectively. In vivo biodistribution indicated high uptake in adrenals (5.4), heart (1.5), lungs (1.5), kidney (1.5) %ID/g at 6 h p.i. In the central nervous system (CNS), the olfactory bulbs displayed the highest uptake; up to six times the activity in blood. Pre-administration of unlabeled CLINDE, PK11195 and Ro 5-4864 (1 mg/kg) reduced the uptake of [(123)I]-CLINDE by 70-55% in olfactory bulbs. In the kidney and heart, a reduction of 60-80% ID/g was observed, while an increase was observed in the adrenals requiring 10 mg/kg for significant displacement. Flumazenil had no effect on uptake in peripheral organs and brain. Metabolite analysis indicated >90% of the radioactivity in the above tissues was intact [(123)I]-CLINDE.


CONCLUSIONS
[(123)I]-CLINDE displays high and selective uptake for the PBBS and warrants further development as a probe for imaging PBBS using single photon emission computed tomography (SPECT).
Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, PMB 1 Menai, NSW 2234 Sydney, Australia. mfp@ansto.gov.au
Filomena
F
Mattner
Karine
K
Mardon
Andrew
A
Katsifis
D000311:Adrenal Glands / Q000000981:diagnostic imaging / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D007425:Intracellular Membranes / Q000000981:diagnostic imaging / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D014018:Tissue Distribution
C504993:6-chloro-2-(4'-iodophenyl)-3-(N,N-diethyl)imidazo(1,2-a)pyridine-3-acetamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007457:Iodine Radioisotopes; D011963:Receptors, GABA-A; D001569:Benzodiazepines