Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D-2 receptor occupancy of olanzapine in rats

A mechanism-based PK-PD model was developed to predict the time course of dopamine D-2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug. A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D2RO profile obtained experimentally at various doses (0.01-40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D-2 receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling . Plasma, brain concentration profiles and time course of D2RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and in vitro values from literature. This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D2RO in rats. Moreover, this modeling framework can be applied to scale the in vitro and preclinical information to clinical receptor occupancy

Not all partial dopamine D2 receptor agonists are the same in treating schizophrenia. Exploring the effects of bifeprunox and aripiprazole using a computer model of a primate striatal dopaminergic synapse

Species differences in physiology and unique active human metabolites contribute to the limited predictive value of preclinical rodent models for many central nervous system (CNS) drugs. In order to explore possible drivers for this translational disconnect, we developed a computer model of a dopaminergic synapse that simulates the competition among three agents and their binding to pre- and postsynaptic receptors, based on the affinities for their targets and their actual concentrations. The model includes presynaptic autoreceptor effects on neurotransmitter release and modulation by presynaptic firing frequency and is calibrated with actual experimental data on free dopamine levels in the striatum of the rodent and the primate. Using this model, we simulated the postsynaptic dopamine D2 receptor activation levels of bifeprunox and aripiprazole, two relatively similar dopamine D2 receptor agonists. The results indicate a substantial difference in dose–response for the two compounds when applying primate calibration parameters as opposed to rodent calibration parameters. In addition, when introducing the major human and rodent metabolites of aripiprazole with their specific pharmacological activities, the model predicts that while bifeprunox would result in a higher postsynaptic D2 receptor antagonism in the rodent, aripiprazole would result in a higher D2 receptor antagonism in the primate model. Furthermore, only the highest dose of aripiprazole, but not bifeprunox, reaches postsynaptic functional D2 receptor antagonism similar to 4 mg haloperidol in the primate model. The model further identifies a limited optimal window of functionality for dopamine D2 receptor partial agonists. These results suggest that computer modeling of key CNS processes, using well-validated calibration paradigms, can increase the predictive value in the clinical setting of preclinical animal model outcomes

Development of new strategies for the synthesis of radiotracers labeled with short-lived isotopes: application to 11C and 13N

S'ha desenvolupat una nova estratègia per la síntesi ràpida i eficient de L-[metil-11C]metionina basada en el captive solvent method. La reacció de L-homocisteína (dissolució bàsica en aigua/etanol 1:1) amb [11C]CH3I en un loop de HPLC va permetre la formació del radiotraçador desitjat amb elevat rendiment radioquímic (38.4 ± 4.1%) en un temps curt (90%) és el propi procés de bombardeig, probablement degut a la combustió (causada per les altes temperatures i pressions assolides durant la irradiació) dels compostos que contenen carboni i que es troben al gas irradiat (o a l'interior del blanc). Es van establir procediments generals per realitzar abans, durant i després de la radiosíntesi per prevenir la contaminació exterior i, d'aquesta manera, augmentar l'activitat específica dels radiotraçadors sintetitzats.En quant al marcatge amb nitrogen-13, s'ha desenvolupat un procés totalment automàtic per a la producció de [13N]NO2- a partir de [13N]NO3- generat en el ciclotró. El precursor radioactiu [13N]NO2- s'ha utilitzat per la radiosíntesi de compostos amb interès biològic com ara S-nitrosotiols (donadors de NO.), N-nitrosamines (molècules amb potencials efectes carcinogènics) i azo compostos (amb possible aplicació com a radiotraçadors per a la detecció in vivo de plaques de β-amiloide). En tots els casos es van obtenir excel·lents conversions radioquímiques (48.7% - 74.5% per S-[13N]nitrosotiols, 45.6% - 53.4% per N-[13N]nitrosamines i 40.0% - 58.3% per 13N-azo compostos) i bons rendiments radioquímics (33.8% - 60.6% per S-[13N]nitrosotiols, 34.0% - 37.8% per N-[13N]nitrosamines i 20.4% - 47.2% per 13N-azo compostos). A més a més, s'ha dissenyat i implementat un mòdul automàtic amb control remot pel marcatge de molècules amb 13N.Se ha desarrollado una nueva estrategia para la síntesis rápida y eficiente de L-[metil-11C]metionina basada en el captive solvent method. La reacción de L-homocisteína (disolución básica en agua/etanol 1:1) con [11C]CH3I en un loop de HPLC permitió la formación del radiotrazador deseado con elevado rendimiento radioquímico (38.4 ± 4.1%) en un tiempo corto (90%) es el propio proceso de bombardeo, probablemente debido a la combustión (causada por las altas temperaturas y presiones alcanzadas durante la irradiación) de los compuestos que contienen carbono y que se encuentran presentes en el gas irradiado (o en el mismo cuerpo del blanco). Se establecieron procedimientos generales para realizar antes, durante y con posterioridad a la radiosíntesis para prevenir la contaminación exterior y, de esta manera, aumentar la actividad específica de los radiotrazadores sintetizados.Respecto al marcaje con nitrógeno-13, se ha desarrollado un proceso totalmente automático para la producción de [13N]NO2- a partir del [13N]NO3- generado en el ciclotrón. El precursor radiactivo [13N]NO2- se ha utilizado para la radiosíntesis de compuestos con interés biológico tales como S-nitrosotioles (donadores de NO.), N-nitrosaminas (moléculas con potenciales efectos carcinogénicos) y azo compuestos (con posible aplicación como radiotrazadores para la detección in vivo de placas de β-amiloide). En todos los casos se obtuvieron excelentes conversiones radioquímicas (48.7% - 74.5% para S-[13N]nitrosotioles, 45.6% - 53.4% para N-[13N]nitrosaminas y 40.0% - 58.3% para 13N-azo compuestos) y buenos rendimientos radioquímicos (33.8% - 60.6% para S-[13N]nitrosotioles, 34.0% - 37.8% para N-[13N]nitrosaminas y 20.4% - 47.2% para 13N-azo compuestos). Además, se ha diseñado e implementado un módulo automático con control remoto para el marcaje de moléculas con 13N.A new strategy for the fast and efficient synthesis of L-[methyl-11C]methionine based on the captive solvent method has been developed. The in loop reaction of a basic water/ethanol 1:1 solution of L-homocysteine with [11C]CH3I led to the formation of the desired radiotracer with high radiochemical yield (38.4 ± 4.1%) in short production time (90%) was shown to be generated during the bombardment process, probably due to the combustion (caused by high temperature and pressure during irradiation) of carbon carrier compounds present in the irradiated gas (or target body). General procedures to be performed before, during and after the radiosynthesis were established to prevent external contamination and to improve the specific radioactivity of 11C-labeled radiotracers synthesized from [11C]CH3I produced via the "wet" method. Concerning 13N-labeling, a fully automatic process for the production of [13N]NO2- from cyclotron generated [13N]NO3- has been developed. The radioactive precursor [13N]NO2- has been used for the synthesis of biologically interesting 13N-labeled compounds such as S-nitrosothiols (well-known NO. donors), N-nitrosamines (molecules with potent carcinogenic effects) and azo compounds (with putative application as imaging probes for in vivo detection of β-amyloid plaques). In all cases, excellent radiochemical conversion (48.7% - 74.5% for S-[13N]nitrosothiols, 45.6% - 53.4% for N-[13N]nitrosamines and 40.0% - 58.3% for 13N-labeled azo compounds) and good radiochemical yields (33.8% - 60.6% for S-[13N]nitrosothiols, 34.0% - 37.8% for N-[13N]nitrosamines and 20.4% - 47.2% for 13N-labeled azo compounds) were achieved. An automatic remote controlled synthesis module for the preparation of 13N-labeled structures has been designed and implemented

Quantification of dopaminergic neurotransmission SPECT studies with 123 l-labelled radioligands

Dopaminergic neurotransmission SPECT studies with 123I-labelled radioligands can help in the diagnosis of neurological and psychiatric disorders such as Parkinson¿s disease and schizophrenia. Nowadays, interpretation of SPECT images is based mainly on visual assessment by experienced observers. However, a quantitative evaluation of the images is recommended in current clinical guidelines. Quantitative information can help diagnose the disease at the early pre-clinical stages, follow its progression and assess the effects of treatment strategies. SPECT images are affected by a number of effects that are inherent in the image formation: attenuation and scattering of photons, system response and partial volume effect. These effects degrade the contrast and resolution of the images and, as a consequence, the real activity distribution of the radiotracer is distorted. Whilst the photon emission of 123I is dominated by a low-energy line of 159 keV, it also emits several high-energy lines. When 123I-labelled radioligands are used, a non-negligible fraction of high-energy photons undergoes backscattering in the detector and the gantry and reaches the detector within the energy window. In this work, a complete methodology for the compensation of all the degrading effects involved in dopaminergic neurotransmission SPECT imaging with 123I is presented. The proposed method uses Monte Carlo simulation to estimate the scattered photons detected in the projections. For this purpose, the SimSET Monte Carlo code was modified so as to adapt it to the more complex simulation of high-energy photons emitted by 123I. Once validated, the modified SimSET code was used to simulate 123I SPECT studies of an anthropomorphic striatal phantom using different imaging systems. The projections obtained showed that scatter is strongly dependent on the imaging system and comprises at least 40% of the detected photons. Applying the new methodology demonstrated that absolute quantification can be achieved when the method includes accurate compensations for all the degrading effects. When the method did not include correction for all degradations, calculated values depended on the imaging system, although a linear relationship was found between calculated and true values. It was also found that partial volume effect and scatter corrections play a major role in the recovery of nominal values. Despite the advantages of absolute quantification, the computational and methodological requirements needed severely limit the possibility of application in clinical routine. Thus, for the time being, absolute quantification is limited to academic studies and research trials. In a clinical context, reliable, simple and rapid methods are needed, thus, semi-quantitative methods are used. Diagnosis also requires the establishment of robust reference values for healthy controls. These values are usually derived from a large data pool obtained in multicentre clinical trials. The comparison between the semi-quantitative values obtained from a patient and the reference is only feasible if the quantitative values have been previously standardised, i.e. they are independent of the gamma camera, acquisition protocol, reconstruction parameters and quantification procedure applied. Thus, standardisation requires that the calculated values are compensated somehow for all the image-degrading phenomena. In this thesis dissertation, a methodology for the standardisation of the quantitative values extracted from dopaminergic neurotransmission SPECT studies with 123I is evaluated using Monte Carlo simulation. This methodology is based on the linear relationship found between calculated and true values for a group of studies corresponding to different subjects with non-negligible anatomical and tracer uptake differences. Reconstruction and quantification methods were found to have a high impact on the linearity of the relationship and on the accuracy of the standardised results