Radiosynthesis and validation of ¹⁸F-FP-CMT, a phenyltropane with superior properties for imaging the dopamine transporter in living brain.
To date there is no validated, (18)F-labeled dopamine transporter (DAT) radiotracer with a rapid kinetic profile suitable for preclinical small-animal positron emission tomography (PET) studies in rodent models of human basal ganglia disease. Herein we report radiosynthesis and validation of the phenyltropane (18)F-FP-CMT. Dynamic PET recordings were obtained for (18)F-FP-CMT in six untreated rats, and six rats pretreated with the high-affinity DAT ligand GBR 12909; mean parametric maps of binding potential (BPND) relative to the cerebellum reference region, and maps of total distribution volume (VT) relative to the metabolite-corrected arterial input were produced. (18)F-FP-CMT BPND maps showed peak values of ∼4 in the striatum, versus ∼0.4 in the vicinity of the substantia nigra. Successive truncation of the PET recordings indicated that stable BPND estimates could be obtained with recordings lasting only 45 minutes, reflecting rapid kinetics of (18)F-FP-CMT. Pretreatment with GBR 12909 reduced the striatal binding by 72% to 76%. High-performance liquid chromatography analysis revealed rapid metabolism of (18)F-FP-CMT to a single, non-brain penetrant hydrophilic metabolite. Total distribution of volume calculated relative to the metabolite-corrected arterial input was 4.4 mL/g in the cerebellum. The pharmacological selectivity of (18)F-FP-CMT, rapid kinetic profile, and lack of problematic metabolites constitute optimal properties for quantitation of DAT in rat, and may also predict applicability in human PET studies.
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich Alexander University, Erlangen, Germany.
Paul
P
Cumming
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich Alexander University, Erlangen, Germany.
Simone
S
Maschauer
Department of Chemistry, Universitetet i Oslo & Norsk Medisinisk Syklotronsenter AS, Oslo, Norway.
Patrick J
PJ
Riss
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
Nuska
N
Tschammer
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
Stefanie K
SK
Fehler
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
Markus R
MR
Heinrich
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich Alexander University, Erlangen, Germany.
Torsten
T
Kuwert
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich Alexander University, Erlangen, Germany.
Olaf
O
Prante
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis*; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals