Quantification of D2-like dopamine receptors in the human brain with 18F-desmethoxyfallypride.
Substituted benzamides such as (11)C-raclopride or (123)I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D(2)-like dopamine (DA) receptors. (18)F-Desmethoxyfallypride ((18)F-DMFP) is a benzamide tracer with the advantage of an (18)F label. We optimized the synthesis and evaluated (18)F-DMFP in PET studies on healthy human volunteers.


METHODS
The affinity of DMFP for D(2)-like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand (3)H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 +/- 54 MBq (mean +/- SD) (18)F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods).


RESULTS
The mean inhibition constant (K(i)) of DMFP was 15 +/- 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods.


CONCLUSIONS
Our study demonstrates that (18)F-DMFP is a highly reliable tracer for PET imaging of D(2)-like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the (18)F label and the favorable imaging properties, (18)F-DMFP could become an efficient substitute for (11)C-raclopride in a clinical context.
Gründer
Gerhard
G
Department of Psychiatry, University of Mainz, Mainz, Germany. gruender@mail.uni-mainz.de
Siessmeier
Thomas
T
Piel
Markus
M
Vernaleken
Ingo
I
Buchholz
Hans-Georg
HG
Zhou
Yun
Y
Hiemke
Christoph
C
Wong
Dean F
DF
Rösch
Frank
F
Bartenstein
Peter
P
D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012457:Salicylamides / Q000097:blood / Q000493:pharmacokinetics*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C100958:desmethoxyfallypride