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We have previously identified a problem related to the use of the reference tissue model for quantification of the high affinity dopamine D2/D3 receptor SPECT tracer [123I]epidepride. It has been noted that quantification of this tracer could be compromised by the presence of lipophilic metabolites crossing the blood-brain barrier. Using kinetic modelling with separate plasma input functions for parent tracer and metabolites, we have now investigated the effect that the metabolites would have on reference tissue modelling. To overcome the problem of poor identifiability of the metabolite rate constants, we have also investigated methods to obtain a better estimate of these rate constants by fitting the time-activity curves for two different brain regions simultaneously, and also by using two different models simultaneously. Our results show that the inclusion of the metabolites in the model for [123I]epidepride does improve the consistency of the results, suggesting that the metabolites do in fact enter the brain. Also, simultaneous modelling did reduce the variability of the metabolite rate constants, however this did not actually improve the performance of the model.