Continuous intravenous infusion of iodine-123-IBZM for SPECT determination of human brain dopamine receptor occupancy by antipsychotic agent RWJ-37796.
PET has shown that dose-dependent in vivo occupancy of dopamine receptors by antipsychotic drugs is associated with clinical response to antipsychotic agents and the production of extrapyramidal side effects. We studied the feasibility of administering [123I]IBZM as a bolus plus continuous infusion over 8 hr to achieve unchanging regional brain activity levels, and the application of [123I]IBZM continuous infusion to examine the effects of the antipsychotic agent RWJ-37796, on striatal activity in humans.


METHODS
Five healthy male subjects received a bolus of [123I]IBZM followed by a continuous infusion at a bolus (mCi):infusion (mCi/hr) ratio of 6:1. Serial SPECT images were obtained every 2-3 min for a total of 8 hr with a 1-2 hr break in the scanning session. Serial venous blood samples were obtained every 30 min for the duration of the study. All five subjects achieved unchanging plasma [123I]IBZM and striatal brain-activity levels over the 300-420 min postinitiation of tracer infusion. Two subjects achieved flat brain time-activity curves later than the others, suggesting the bolus-to-infusion ratio was slightly high. An additional six healthy male subjects received a similar bolus plus constant infusion of [123I]IBZM. RWJ-37796 (0.04 mg/kg) was administered intravenously 157 +/- 13.7 min after the initiation of [123I]IBZM infusion. Serial SPECT brain images, serum prolactin and extrapyramidal side effect ratings were obtained for an additional 330 min.


RESULTS
All six subjects demonstrated rapid and marked reduction of striatal activity following RWJ-37796 without return of striatal activity to baseline levels over the 5.5 hr of continued [123I]IBZM administration. Estimated receptor occupancy by RWJ-37796 was 57% +/- 5% (range 47%-67%). Prolactin was only transiently increased in all subjects by 1054% +/- 1084% over baseline. One subject experienced moderate extrapyramidal symptoms (akasthisia) during RWJ-37796 injection.


CONCLUSIONS
SPECT imaging during continuous [123I]IBZM infusion provides a powerful within-scan method for determining both temporal binding characteristics and receptor occupancy of striatal dopamine receptors by antipsychotic agents.
Seibyl
J P
JP
Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT 06520-8042, USA.
Zea-Ponce
Y
Y
Brenner
L
L
Baldwin
R M
RM
Krystal
J H
JH
Offord
S J
SJ
Mochoviak
S
S
Charney
D S
DS
Hoffer
P B
PB
Innis
R B
RB
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D003287:Contrast Media / Q000008:administration & dosage; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D006801:Humans; D007262:Infusions, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000187:drug effects; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon
D014150:Antipsychotic Agents; D001549:Benzamides; D003287:Contrast Media; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D010879:Piperazines; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide; C086897:mazapertine succinate