Metabolism an autoradiographic evaluation of [18F]FE@CIT:: a Comparison with [123I]β-CIT and [123I]FP-CIT

Purpose: Since the late 1980s, cocaine analogues based on the phenyltropane structure, such as [C-11]CFT and [I-123]beta-CIT have been used for the imaging of the dopamine transporter. FE@CIT (fluoropropyl ester) and FP-CIT (N-fluoropropyl derivative) are further analogues. The aim of this study was to (1) evaluate and compare the metabolic stability of beta-CIT, FP-CIT and FE@CIT against carboxyl esterases and (2) evaluate selectivity of [F-18]FE@CIT compared to [I-123]beta-CIT and [I-123]FP-CIT using autoradiography. Methods: In vitro enzymatic hydrolysis assays were performed using different concentrations of beta-CIT, FE@CIT and FP-CIT with constant concentrations of carboxyl esterase. Autoradiography was performed on coronal 20-mu m rat brain sections incubated with different radioactivity concentrations of [I-123]beta-CIT, [123 I]FP-CIT or [F-18]FE@CIT and, additionally, with 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [serotonin transporter (SERT)] and nisoxetine [norepinephrine transporter (NET)] for blocking experiments. Results: In vitro assays showed Michaelis-Menten constants of 175 mu mol (beta-CIT), 183 mu mol (FE@CIT) and 521 mu mol (FP-CIT). Limiting velocities were 0.1005 mu mol/min (beta-CIT), 0.1418 mu mol/min (FE@CIT) and 0.1308 mu mol/min (FP-CIT). This indicates a significantly increased stability of FP-CIT, whereas carboxyl esterase stability of beta-CIT and FE@CIT showed no significant difference. Autoradiographic analyses revealed a good correlation between dopamine transporter (DAT)-rich regions and the uptake pattern of FE@CIT. Blocking experiments showed a higher DAT selectivity for [F-18]FE@CIT than for the other two tracers. Conclusion: We found that (1) the metabolic stability of FE@CIT was comparable to that of beta-CIT, whereas FP-CIT showed higher resistance to enzymatic hydrolysis; and (2) the overall uptake pattern of [F-18]FE@CIT on brain slices was comparable to that of[I-123]beta-CIT and [I-123]FPCIT. After blocking of NET and SERT binding, a significantly higher DAT selectivity was observed for [F-18]FE@CIT. Hence, [F-18]FE@CIT may be of interest for further clinical application. (C) 2008 Elsevier Inc. All rights reserved.