Tissue distribution of radioiodinated FAUC113: assessment of a pyrazolo(1,5-a) pyridine based dopamine D4 receptor radioligand candidate.
OBJECTIVE
Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-(131)I-FAUC 113 in Sprague-Dawley rats.


METHODS
Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radio-hplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and ex-vivo autoradiography on a mu-Imager system.


RESULTS
7-(131)I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603 +/- 0.047% ID/g, n = 4) and liver (0.357 +/- 0.070% ID/g, n = 4) at 10 min p.i.; 7-(131)I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36 +/- 0.15 (n = 4). In-vivo stability of 7-(131)I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57 +/- 0.13 at 10 min p.i. (n = 6). Coinjection with L-750667 could not suppress any putative specific binding of 7-(131)I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand.


CONCLUSIONS
Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brain barrier permeability.
Prante
O
O
Labor für Molekulare Bildgebung, Nuklearmedizinische Klinik, Friedrich-Alexander Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany. olaf.prante@nuklear.imed.uni-erlangen.de
Hocke
C
C
Löber
S
S
Hübner
H
H
Gmeiner
P
P
Kuwert
T
T
D000818:Animals; D006207:Half-Life; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007668:Kidney / Q000000981:diagnostic imaging; D008657:Metabolic Clearance Rate; D011720:Pyrazoles / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors; D014018:Tissue Distribution
C118215:3-(4-(4-chlorophenyl)piperazinylmethyl)pyrazolo(1,5-a)pyridine; D007457:Iodine Radioisotopes; D011720:Pyrazoles; D011725:Pyridines; D050638:Receptors, Dopamine D4