PET Imaging of the 5-HT2A Receptor System: A Tool to Study the Receptor’s In Vivo Brain Function

Herth, Matthias M.; Knudsen, Gitte Moos

doi:10.1007/978-3-319-70474-6_5

Cited by 11 publications

(21 citation statements)

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“…Apart from efflux transporter expression and activity, inter-species differences in receptor abundances or metabolic pathways are factors that may have a crucial impact on the translational validation of PET tracers [ 38 , 39 ]. Densities of 5-HT 2A , 5-HT 7 and D 2/3 receptors in the respective receptor-rich regions of rodent, pig and human brain are summarized from literature data in Additional file 1 : Table S4 [ 28 , 40 – 42 ]. Densities of 5-HT 7 receptors in rat and pig thalamus are very close, so the differences in metabolism between rats and pigs are a more likely explanation for the discrepant results of [ 11 C]Cimbi-701 and [ 11 C]Cimbi-717 evaluation in these two species.…”

Section: Discussionmentioning

confidence: 99%

Blocking of efflux transporters in rats improves translational validation of brain radioligands

et al. 2020

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Background Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs. Methods PET tracers targeting serotonin 5-HT2A receptors ([18F]MH.MZ, [18F]Altanserin, [11C]Cimbi-36, [11C]Pimavanserin), serotonin 5-HT7 receptors ([11C]Cimbi-701, [11C]Cimbi-717 and [11C]BA-10) and dopamine D2/3 receptors ([18F]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs. Results Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, results for five out of eight tracers justified further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition. Conclusions P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition.

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Section: Discussionmentioning

confidence: 99%

Blocking of efflux transporters in rats improves translational validation of brain radioligands

et al. 2020

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“…). A value > 5 should be observed to guarantee selective imaging

{tBR}_{italictarget / italicoff - italictarget} = S x D = ((), \frac{K_{D, off - target}}{K_{D, target}}) x ((), \frac{B_{avail, target}}{B_{avail, off - target}})

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Section: Discussionmentioning

confidence: 99%

Radiosynthesis and preclinical evaluation of [¹¹C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT₇ receptors

'Estrade

Shalgunov

Edgar

et al. 2020

Labelled Comp Radiopharmac

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The serotonin 7 (5-HT 7 ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target.Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT 7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [ 11 C]Cimbi-701. Cimbi-701 was synthesized in a one-step procedure starting from SB-269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [ 11 C]Cimbi-701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5-HT 7 and σ receptor blocking studies. P-gp efflux transporter dependency was investigated using elacridar.[ 11 C]Cimbi-701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5-HT 7 (K i = 18 nM), σ-1 (K i = 9.2 nM) and σ-2 (K i = 1.6 nM) receptors. In rats, [ 11 C]Cimbi-701 acted as a strong P-gp substrate. After P-gp inhibition, rat brain uptake could specifically be blocked by 5-HT 7 and σ receptor ligands. In pig, high brain uptake and specific 5-HT 7 and σreceptor binding was found for [ 11 C]Cimbi-701 without P-gp inhibition.Finally, low brain uptake was found in baboons. Both the specific σ-receptor binding and the low brain uptake of [ 11 C]Cimbi-701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5-HT 7 receptor imaging might be possible when more selective non-P-gp substrates are identified.

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“…Apart from e ux transporter expression and activity, inter-species differences in receptor abundances or metabolic pathways are factors that may have a crucial impact on the translational validation of PET tracers [38,39]. Densities of 5-HT 2A , 5-HT 7 and D 2/3 receptors in the respective receptor-rich regions of rodent, pig and human brain are summarized from literature data in Supplementary Table S4 [28,[40][41][42]. Densities of 5-HT 7 receptors in rat and pig thalamus are very close, so the differences in metabolism between rats and pigs are a more likely explanation for the discrepancies observed in the results of [ 11 C]Cimbi-701 and [ 11 C]Cimbi-717 evaluation between these two species.…”

Section: Discussionmentioning

confidence: 99%

Blocking of Efflux Transporters in Rats Improves Translational Validation of Brain Radioligands

Shalgunov

Xiong

L'Estrade

et al. 2020

Preprint

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Background: Positron Emission Tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs.Methods: PET tracers targeting serotonin 5-HT2A receptors ([18F]MH.MZ, [18F]Altanserin, [11C]Cimbi-36, [11C]Pimavanserin), serotonin 5-HT7 receptors ([11C]Cimbi-701, [11C]Cimbi-717 and [11C]BA-10) and dopamine D2/3 receptors ([18F]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs.Results: Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, five out of eight tracers justifyied further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition.Conclusions: P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition.

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PET Imaging of the 5-HT2A Receptor System: A Tool to Study the Receptor’s In Vivo Brain Function

Cited by 11 publications

References 224 publications

Blocking of efflux transporters in rats improves translational validation of brain radioligands

Blocking of efflux transporters in rats improves translational validation of brain radioligands

Radiosynthesis and preclinical evaluation of [¹¹C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT₇ receptors

Blocking of Efflux Transporters in Rats Improves Translational Validation of Brain Radioligands

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PET Imaging of the 5-HT2A Receptor System: A Tool to Study the Receptor’s In Vivo Brain Function

Cited by 11 publications

References 224 publications

Blocking of efflux transporters in rats improves translational validation of brain radioligands

Blocking of efflux transporters in rats improves translational validation of brain radioligands

Radiosynthesis and preclinical evaluation of [11C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT7 receptors

Blocking of Efflux Transporters in Rats Improves Translational Validation of Brain Radioligands

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Radiosynthesis and preclinical evaluation of [¹¹C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT₇ receptors