At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.

During treatment with clinical doses of paroxetine or citalopram, approximately 80% of 5-HTT receptors are occupied. This change in 5-HTT binding potential is greater than the known physiological range of changes in 5-HTT binding potential but may be necessary for some therapeutic effects.

In vivo imaging of dopamine D2 receptors with agonist (as opposed to the more commonly employed antagonist) radiotracers could provide important information on the high-affinity (functional) state of the D2 receptor in illnesses such as schizophrenia, movement disorders, and addictions. We report here the radiosynthesis and evaluation of the potent D2 agonist (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, (+)-3, labeled with carbon-11, as a potential radiotracer for imaging the high-affinity state of dopamine D2 receptors with positron emission tomography (PET). [(11)C]-(+)-3 was reliably synthesized in the quantities and at the specific activities and radiochemical purities required for human PET studies. Ex vivo biodistribution studies in rat brain demonstrated that [(11)C]-(+)-3 crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer that maps dopamine D2 receptors. The binding of [(11)C]-(+)-3 was saturable and demonstrated an excellent signal-to-noise ratio as measured by its striatum-to-cerebellum ratio of 5.6, 60 min postinjection. The binding was highly stereospecific, and blocking and displacement studies were consistent with selective and specific binding to the dopamine D2 receptors. Further, [(11)C]-(+)-3 showed marked and appropriate sensitivity to both increases and decreases in the levels of endogenous dopamine. Brain radioactive metabolite and physicochemical measurements are in full accord with the desired properties of a neuroreceptor imaging agent for PET. All of the above, coupled with the documented full D2 agonistic properties of (+)-3, strongly indicate that [(11)C]-(+)-3 is a leading candidate radiotracer for the imaging of the dopamine D2 high-affinity state using PET in human subjects.

[(11) C]-DASB, namely [(11) C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [(11)C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k(3) and k(4) were estimated with poor precision. Only the ratio k(3)/k(4) was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k(3)/k(4) estimates was 80 minutes. For routine use of [(11)C]-DASB, several simplified methods using the cerebellum as a reference region to estimate nonspecific binding were also evaluated. The transient equilibrium, the linear graphical analysis, the ratio of target to reference region, and the simplified reference tissue methods all gave binding potential values consistent with those obtained with the 2CM. The suitability of [(11)C]-DASB for research on the SERT using PET is thus supported by the observations that tissue data can be described using a kinetic analysis and that simplified quantitative methods, using the cerebellum as reference, provide reliable estimates of SERT binding parameters.

Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.

Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio) b enzylamine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (D ASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [11C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [11C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans.

PET and: markers for the pre- and postsynaptic neurons were used to study the dopamine system in vivo in Huntington's disease. The radioligands used were [11C]SCH 23390 for D1-receptors, [11C]raclopride for D2-receptors and [11C]beta-CIT for dopamine transporters. Five patients with Huntington's disease and five matched controls were recruited. Brain anatomy was examined by MRI. The findings in patients were as follows. Postsynaptic D1- and D2-receptor densities were similarly reduced in the striatum. A reduction in D1-receptor density was shown in the temporal cortex; it draws attention to the cortical degeneration in relation to the cognitive deficits observed in Huntington's disease. The reduction of D1- and D2-receptor binding potentials in the striatum correlated significantly with increasing duration of illness. The correlation between the duration of illness and decline of D1- and D2-receptors make these receptors valuable as quantitative markers for the Huntington's disease degenerative process. Besides postsynaptic changes, a significant 50% decrease of [11C]beta-CIT binding to the dopamine transporter was found in the striatum. A reduced striatal blood flow in Huntington's disease cannot be excluded and could account for a small part of the decrease in [11C]beta-CIT binding. We suggest that the finding reflects a loss of presynaptic terminals or a reduced expression of dopamine transporter in the nigrostriatal dopaminergic system in Huntington's disease.

D(2) receptor binding is a more important factor than chronological age in accounting for variation in cognitive performance across the adult lifespan. Changes in dopaminergic neurotransmission play an important role in aging-related cognitive decline.