Preliminary evaluation of 2-[4-[3-(tert-Butylamino)-2-hydroxypropoxy]phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone ([±]HX-CH 44) as a Selective β1-Adrenoceptor Ligand for PET

International audience(+/-)-3-[11C]Methyl-2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-6 -methoxy-4(3H) quinazolinone ([+/-]-[11C]HX-CH 44) was labeled with carbon-11 using [11C]iodomethane with the corresponding N-demethylated precursor. Then, 30-90 mCi (1.10-3.33 GBq) of pure [11C]HX-CH 44 were obtained 30 min after end of bombardment with specific radioactivities of 500-1,400 mCi/micromol (18.5-51.8 GBq/micromol). Myocardial uptake in dogs was 0.340+/-0.043 pmol/mL tissue per nanomole injected, 10-15 min postinjection. Heart-to-lung ratio was 3 from the 5th to the 30th minute. Only 35% of the myocardial radioactivity could be displaced. Tissue uptake could not be blocked with appropriate compounds. Therefore, (+/-)-[11C]HX-CH 44 does not appear to be a suitable ligand for the study of myocardial beta1-adrenoceptors in positron emission tomography

Bromine-76-Metabromobenzylguanidine: A PET Radiotracer for Mapping Sympathetic Nerves of the Heart

Iodine-123-metaiodobenzylguanidine (MIBG) is used to qualitatively assess heart innervation with single-photon emission computed tomography (SPECT). This approach is clinically useful in the prognostic evaluation of congestive heart failure. To improve quantification of uptake of the tracer using positron emission tomography (PET), we studied the characteristics of the bromoanalog of MIBG. Bromine-76-metabromobenzylguanidine (76Br-MBBG) was prepared from a heteroisotopic exchange between radioactive bromine atoms (noncarrier-added (76Br) BrNH4) and the cold iodine atoms of the precursor metaiodobenzylguanidine. Biodistribution was studied in rats and PET cardiac imaging performed in dogs. Myocardial uptake was high and prolonged in both species (mean half-life in dogs: 580 min). In rats, myocardial uptake was inhibited by desipramine by 64%, whereas after pretreatment with 6- hydroxydopamine uptake was reduced by 84%. In dogs pretreated with 6- hydroxydopamine or with desipramine, a steep washout of the tracer occurred (mean half-life: 136 min and 118 min, respectively). The non-specific uptake plus the passive neuronal diffusion of the tracer could be estimated at about 25%-30% of the total fixation. In dogs, analysis of unchanged 76Br-MBBG in plasma showed that radiotracer metabolism was slow: 60 min after injection, 80% of the radioactivity was related to unchanged 76Br-MBBG. These preliminary findings suggest that 76Br-MBBG could be used to quantitatively assess adrenergic innervation in heart disease using PET. When combined with use of 11C-CGP 12177, cardiac adrenergic neurotransmission can be assessed

Pharmacokinetic-pharmacodynamic modelling: history and perspectives

A major goal in clinical pharmacology is the quantitative prediction of drug effects. The field of pharmacokinetic-pharmacodynamic (PK/PD) modelling has made many advances from the basic concept of the dose-response relationship to extended mechanism-based models. The purpose of this article is to review, from a historical perspective, the progression of the modelling of the concentration-response relationship from the first classic models developed in the mid-1960s to some of the more sophisticated current approaches. The emphasis is on general models describing key PD relationships, such as: simple models relating drug dose or concentration in plasma to effect, biophase distribution models and in particular effect compartment models, models for indirect mechanism of action that involve primarily the modulation of endogenous factors, models for cell trafficking and transduction systems. We show the evolution of tolerance and time-variant models, non- and semi-parametric models, and briefly discuss population PK/PD modelling, together with some example of more recent and complex pharmacodynamic models for control system and nonlinear HIV-1 dynamics. We also discuss some future possible directions for PK/PD modelling, report equations for general classes of novel semi-parametric models, as well as describing two new classes, additive or set-point, of regulatory, additive feedback models in their direct and indirect action variants