6533b7d9fe1ef96bd126d7b7
RESEARCH PRODUCT
68 Ga‐Labelled Tropane Analogues for the Visualization of the Dopaminergic System
Aylin Sibel CankayaSascha HäseliMarkus JokschBernd J. KrauseMarkus PielCarina BergnerJens KurthAndreas WreeHarald H. SitteMarion HolyFrank Röschsubject
Rat modeltropane01 natural sciencesBiochemistrychemistry.chemical_compoundgallium-68Drug DiscoverylipophilicitymedicineGeneral Pharmacology Toxicology and PharmaceuticsradiopharmaceuticalsDopamine transporterPharmacologyFull Paperbiologymedicine.diagnostic_test010405 organic chemistryChemistryOrganic ChemistryDopaminergicdopamine transportersTropaneFull Papers0104 chemical sciencesimaging agents010404 medicinal & biomolecular chemistryPositron emission tomographyLipophilicityLead structurebiology.proteinBiophysicsMolecular MedicineRadionuclide Generatordescription
Abstract The development of radiometal‐labelled pharmaceuticals for neuroimaging could offer great potential due to easier handling during labelling and availability through radionuclide generator systems. Nonetheless, to date, no such tracers are available for positron emission tomography, primarily owing to the challenge of crossing the blood–brain barrier (BBB) and loss of affinity through chelator attachment. We have prepared a variety of 68Ga‐labelled phenyltropanes showing that, through a simple hydrocarbon‐linker, it is possible to introduce a chelator onto the lead structure while maintaining its high affinity for hDAT (human dopamine transporter) and simultaneously achieving adequate lipophilicity. One of the candidates, [68Ga]Ga‐HBED‐hexadiyne‐tropane, showed an IC50 value of 66 nM, together with a log D 7.4 of 0.96. A μPET study in a hemi‐parkinsonian rat model showed a fast wash‐out of the tracer, and no specific uptake in the brain, thus implying an inability to penetrate the BBB.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-12-01 | ChemMedChem |