PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756.
NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.
Abi-Dargham
A
A
Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York State Psychiatric Institute, New York 10032, USA. aadar@neuron.cpmc.columbia.edu
Simpson
N
N
Kegeles
L
L
Parsey
R
R
Hwang
D R
DR
Anjilvel
S
S
Zea-Ponce
Y
Y
Lombardo
I
I
Van Heertum
R
R
Mann
J J
JJ
Foged
C
C
Halldin
C
C
Laruelle
M
M
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001572:Benzofurans / Q000097:blood / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D010215:Papio; D020891:Raclopride; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D012457:Salicylamides / Q000494:pharmacology; D013788:Thalamus / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism; D014055:Tomography, Emission-Computed
D001552:Benzazepines; D001572:Benzofurans; D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D012457:Salicylamides; D020891:Raclopride; C075357:odapipam; D000661:Amphetamine; D004298:Dopamine