Tropane-derived 1 1-labelled and 18F-labelled DAT ligands+

摘要

Positron emission tomography (PET) studies of dopamine transporter (DAT) availability provide valuable insights into the presynaptic integrity of dopaminergic neurons in vivo.1"5 Several key challenges persist in the development of DAT ligands, these are DAT selectivity, due to close homology of the serotonin transporter and the noradrenalin transporter, and slow equilibration of binding, caused by high binding affinity and adverse metabolic degradation. A DAT ligand with ideal characteristics has to be identified.6"14 initial candidates included [11C]nomifen-sine, [18F]GBR13119, D-f/ireo-[11C]methylphenidate and the tropane (1) (—)-/V-[11C]cocaine (2). These suffered from low striatum to cerebellum ratios (1.5-2.4), fast washout and low selectivity.5'6 Despite the equipotent inhibition of DAT, serotonin transporter and noradrenalin transporter, 2 emerged as the lead for DAT radiotracer development regardless of its short biological half-life and low selectivity. Substitution of the benzoate ester by an arene moiety to afford 3-phenyltropanes (3) resulted in a 40 times longer biological half-life.15'16