Initial human PET imaging studies with the dopamine transporter ligand 18F-FECNT.
The aim of this study was to do an initial assessment of the usefulness of 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-(18)F-fluoroethyl)nortropane ((18)F-FECNT) PET scanning in determining in vivo brain dopamine transporter (DAT) density in healthy humans and subjects with Parkinson's disease (PD).


METHODS
We investigated 6 neurologically healthy subjects and 5 PD patients: 2 with mild unilateral disease, 1 with mild-to-moderate bilateral disease, and 2 with moderately severe bilateral disease. The healthy subjects underwent a 3-h PET scan (26 frames) and the PD subjects underwent a 2-h PET scan (23 frames) while (18)F-FECNT was being injected over the first 5 min of the scan. Arterial blood samples were taken throughout scanning for well-counter and metabolite analysis to determine the presence of possible active metabolites. The scans were reconstructed; then we placed spheric regions of interest in the caudate nuclei, putamena, thalami, brain stem, cerebellum, and occipital cortex of each subject. The radioactivity level in each region was calculated for each frame of a subject's PET scan. Then we calculated target tissue-to-cerebellum ratios for each time frame.


RESULTS
The analysis of arterial blood samples revealed that metabolism of the tracer was rapid. The ether-extractable component of the arterial input was >98% pure (18)F-FECNT. The caudate nucleus and putamen exhibited the highest uptake and prolonged retention of the radioligand. They both attained maximum uptake at approximately 90 min, with the healthy subjects' average caudate- and putamen-to-cerebellum ratios (+/-SD) at that time being 9.0 +/- 1.2 and 7.8 +/- 0.7, respectively. The maximal caudate-to-cerebellum ratios for the healthy subjects ranged from 7.6 to 10.5 and their maximal putamen-to-cerebellum ratios ranged from 7.1 to 9.3. The 2 early-stage, unilateral PD patients had, at 90 min, an average right caudate-to-cerebellum ratio of 5.3 +/- 1.1 and a left ratio of 5.9 +/- 0.7 and an average right putamen-to cerebellum ratio of 2.8 +/- 0.1 and a left ratio of 3.0 +/- 0.6. The late-stage PD patients had, at 90 min, an average right caudate-to-cerebellum ratio of 3.7 +/- 0.4 and a left ratio of 3.9 +/- 0 and an average right putamen-to cerebellum ratio of 1.8 +/- 0.1 and a left ratio of 1.8 +/- 0.


CONCLUSIONS
These results indicate that (18)F-FECNT is an excellent candidate radioligand for in vivo imaging of the DAT system in humans. It has a much higher affinity for DAT than for the serotonin transporter and yields the highest peak striatum-to-cerebellum ratios and has among the most favorable kinetics of (18)F-radiolabeled DAT ligands. Having picked up presymptomatic changes in the hemisphere opposite the unaffected side of the body in our early-stage (unilateral) PD patients, it appears that, like other DAT radioligands, it may be able to identify presymptomatic PD.
Davis
Margaret R
MR
PET Center, Emory University, Atlanta, Georgia, USA.
Votaw
John R
JR
Bremner
J Douglas
JD
Byas-Smith
Michael G
MG
Faber
Tracy L
TL
Voll
Ronald J
RJ
Hoffman
John M
JM
Grafton
Scott T
ST
Kilts
Clinton D
CD
Goodman
Mark M
MM
D000328:Adult; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D005240:Feasibility Studies; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D009662:Nortropanes / Q000493:pharmacokinetics*; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed / Q000379:methods*
C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; C493214:SLC6A3 protein, human