Development of radioligands for emission tomography imaging of dopamine D1andbenzodiazepine receptors
Abstract: Brain imaging of dopamine and benzodiazepine (BZ) receptors invivo is of central interest in neuropsychiatric disorders such asschizoprenia, Huntington's disease and epilepsy. The objective was to develop new radioligands for emissiontomography of dopamine D1 and BZ receptors. A series ofnew compounds with origin from Novo Nordisk, belonging to thechemical classes of benzazepines and benzodiazepines, were labelledwith the positron emitting radionuclides 11C and76Br for positron emission tomography (PET), they--emitting radionuclide 123l for single photonemission computed tomography (SPECT) and the longer-livedradionuclides 1251 and 14C for receptorcharacterisation in vitro and metabolite studies. The time course forthe brain distribution of radioactivity was measured by PET or SPECTin the monkey and human brain. Radioligand metabolism measured inplasma was determined by gradient HPLC. 11C-Labelling was performed by N-methylation ofsecondary amines or amides using [11C]methyl iodide or[11C]methyl triflate. 76Br-labelling wasperformed in a Cu+ assisted nucleophilic substitutionreaction or by electrophilic iododestannylation. Radioiodinationswere accomplished using different approaches such asiododediazonization, nucleophilic exchange of radioiodine forbromine, iododestannylation and direct electrophilic substitution onactivated aromatic systems. 14C-labelled benzazepines weresynthesized in several steps starting from [14C]methyliodide. The slow wash-out of the D1 antagonist [76Br]NNC22-0010 from the monkey brain allowed PET measurements over severalhours. Of the seven D1 radioligands examined for PET[11C]NNC 22-0215 was the most slowly metabolised asmeasured in monkey plasma. [11C]NNC 756 and[11C]NNC 112 had the highest striatum to cerebellum ratio.The ratio was 4-5 in human studies. The highly selective radioligand[11C]NNC 112 is the most promising radioligand sinceradioactivity not only in the striatum but also in neocorticalregions reached equilibrium conditions during time of a PET studywhich is of advantage for quantification of D1 receptors inneuropsychiatric disorders. The two structurally closely related BZ agonists NNC 13-8241 andNNC 13 8199 were labelled for in vitro studies and PET/SPECTexaminations. In vitro and in vivo binding studies inrats showed that [1251]NNC 13-8241 binds to BZ receptorswith high affinity and low degree of non-specific binding. SPECTstudies with [1231]NNC 13-8241 and PET studies with[76Br]- and [11C]NNC 13 8199 confirmed the lowdegree of non-specific binding of these radioligands and demonstratedsaturable and reversible binding for central BZ receptors in bothmonkey and man. The metabolism of the radioligands observed in monkeyand human plasma was very slow. The results indicate that[1231]NNC 13-8241 and [76Br]NNC 13-8199 havepotential as radioligands for human emission tomography studies usingquantitative models for which a slow rate of metabolism is ofadvantage. Key words: Dopamine D1 receptors, Benzodiazepine(BZ) receptors, PET, SPECT. Stockholm 1997 ISBN 91-628-2618-2
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