[C-11,I-127] altropane: A highly selective ligand for PET imaging of dopamine transporter sites

The E isomer of I-123-2 beta -carbomethoxy-3 beta-(4-fluorophenyl)prop-1-en -3-yl)nortropane (Altropane(R)) shows high affinity (IC50 = 6.62 +/- 0.78 n mol) and selectivity (DA/5-HT = 25) for DAT sites in the striatum. Recently , dynamic SPECT studies in healthy volunteers and patients with Parkinson d isease demonstrated that the kinetics of striatal accumulation followed a p attern that is characteristic of a reversible tracer with maximal accumulat ion within 30 min after injection. These findings suggested that radiolabel ing Altropane with [C-11] might provide an equivalent and complementary tra cer for PET studies. [I-127] Altropane was treated with HCl to hydrolyze th e methyl ester bond and yield a precursor for [C-11] labeling. Introduction of an [C-11] methyl ester group was achieved by treatment with [C-11] CH3I followed by HPLC purification. Five healthy rhesus monkeys were injected w ith similar to 10 mCi of [I-127,C-11] Altropane and dynamic PET images were acquired over 90 min. Arterial blood samples were collected in parallel wi th imaging and metabolite analysis was performed by HPLC. The PET and metab olite corrected arterial blood data were to calculate k(3)/k(4) by two meth ods: 1) nonlinear least-squares fitting, and 2) a linear graphical method f or reversible ligands. The synthetic procedure yielded high specific activi ty tracer, >1,000 mCi/mu mole, with radiochemical purity >95%. Synthesis ti me was similar to 30 min. The PET images revealed excellent striatal defini tion, with clear separation of caudate nucleus and putamen and minimal accu mulation in brain regions with high 5HT transporter density. Metabolite ana lysis demonstrated that at 60 min after injection, similar to 80% of circul ating tracer was intact [I-127,C-11] Altropane and the remainder was conver ted to polar metabolites. Values for k(3)/k(4) calculated by two analysis m ethods were remarkably similar: Method 1, 3.48 +/- 0.41; Method 2, 3.77 +/- 0.45 (mean +/- SEM, t = 2.31, df = 8, P = 0.64). These results establish t hat Altropane has the important characteristics of: 1) rapid and specific s triatal binding; 2) high selectivity for DA vs. 5-HT transporter sites; 3) reversible binding kinetics; 4) potential for multiple injection studies; 5 ) high efficiency labeling with either [C-11] or [I-123]; 6) applicability for both PET and SPECT. These properties make Altropane an important DAT li gand for both research and clinical applications. Synapse 39:332-342, 2001, (C) 2001 Wiley-Liss, Inc.