Phosphodiesterase 10A PET radioligand development program: from pig to human

Christophe Plisson; David Weinzimmer; Steen Jakobsen; Sridhar Natesan; Cristian Salinas; Shu-Fei Lin; David Labaree; Ming-Qiang Zheng; Nabeel Nabulsi; Tiago Reis Marques; Shitij Kapur; Eiji Kawanishi; Takeaki Saijo; Roger N Gunn; Richard E Carson; Eugenii A Rabiner

doi:10.2967/jnumed.113.131409

Phosphodiesterase 10A PET radioligand development program: from pig to human

Christophe Plisson, David Weinzimmer, Steen Jakobsen, Sridhar Natesan, Cristian Salinas, Shu-Fei Lin, David Labaree, Ming-Qiang Zheng, Nabeel Nabulsi, Tiago Reis Marques, Shitij Kapur, Eiji Kawanishi, Takeaki Saijo, Roger N Gunn, Richard E Carson, Eugenii A Rabiner

The Imanova Centre for Imaging Sciences

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

Abstract

Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported 11C-MP-10. Methods: On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either 11C via N-methylation or with 18F through an SN2 reaction, in the case of IMA102. These candidates were compared with 11C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, 11C-IMA106 and 11C-IMA107 were taken into further evaluation and comparison with 11C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. Results: All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that 11C-IMA107 and 11C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of 11C-IMA107 and 11C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of 11C-IMA107 and 11C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. Conclusion: 11C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of 11C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that 11C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.

Original language	English
Pages (from-to)	595-601
Number of pages	7
Journal	Journal of Nuclear Medicine
Volume	55
Issue number	4
Early online date	10 Mar 2014
DOIs	https://doi.org/10.2967/jnumed.113.131409
Publication status	Published - 1 Apr 2014

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Plisson, C., Weinzimmer, D., Jakobsen, S., Natesan, S., Salinas, C., Lin, S.-F., Labaree, D., Zheng, M.-Q., Nabulsi, N., Marques, T. R., Kapur, S., Kawanishi, E., Saijo, T., Gunn, R. N., Carson, R. E., & Rabiner, E. A. (2014). Phosphodiesterase 10A PET radioligand development program: from pig to human. Journal of Nuclear Medicine, 55(4), 595-601. https://doi.org/10.2967/jnumed.113.131409

@article{8114b2afe74b4a7abe25e7e88ff7fc05,

title = "Phosphodiesterase 10A PET radioligand development program: from pig to human",

abstract = "Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported 11C-MP-10. Methods: On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either 11C via N-methylation or with 18F through an SN2 reaction, in the case of IMA102. These candidates were compared with 11C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, 11C-IMA106 and 11C-IMA107 were taken into further evaluation and comparison with 11C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. Results: All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that 11C-IMA107 and 11C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of 11C-IMA107 and 11C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of 11C-IMA107 and 11C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. Conclusion: 11C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of 11C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that 11C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.",

author = "Christophe Plisson and David Weinzimmer and Steen Jakobsen and Sridhar Natesan and Cristian Salinas and Shu-Fei Lin and David Labaree and Ming-Qiang Zheng and Nabeel Nabulsi and Marques, {Tiago Reis} and Shitij Kapur and Eiji Kawanishi and Takeaki Saijo and Gunn, {Roger N} and Carson, {Richard E} and Rabiner, {Eugenii A}",

year = "2014",

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doi = "10.2967/jnumed.113.131409",

language = "English",

volume = "55",

pages = "595--601",

journal = "Journal of Nuclear Medicine",

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Plisson, C, Weinzimmer, D, Jakobsen, S, Natesan, S, Salinas, C, Lin, S-F, Labaree, D, Zheng, M-Q, Nabulsi, N, Marques, TR , Kapur, S, Kawanishi, E, Saijo, T, Gunn, RN, Carson, RE & Rabiner, EA 2014, 'Phosphodiesterase 10A PET radioligand development program: from pig to human', Journal of Nuclear Medicine, vol. 55, no. 4, pp. 595-601. https://doi.org/10.2967/jnumed.113.131409

TY - JOUR

T1 - Phosphodiesterase 10A PET radioligand development program

T2 - from pig to human

AU - Plisson, Christophe

AU - Weinzimmer, David

AU - Jakobsen, Steen

AU - Natesan, Sridhar

AU - Salinas, Cristian

AU - Lin, Shu-Fei

AU - Labaree, David

AU - Zheng, Ming-Qiang

AU - Nabulsi, Nabeel

AU - Marques, Tiago Reis

AU - Kapur, Shitij

AU - Kawanishi, Eiji

AU - Saijo, Takeaki

AU - Gunn, Roger N

AU - Carson, Richard E

AU - Rabiner, Eugenii A

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported 11C-MP-10. Methods: On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either 11C via N-methylation or with 18F through an SN2 reaction, in the case of IMA102. These candidates were compared with 11C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, 11C-IMA106 and 11C-IMA107 were taken into further evaluation and comparison with 11C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. Results: All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that 11C-IMA107 and 11C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of 11C-IMA107 and 11C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of 11C-IMA107 and 11C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. Conclusion: 11C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of 11C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that 11C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.

AB - Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported 11C-MP-10. Methods: On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either 11C via N-methylation or with 18F through an SN2 reaction, in the case of IMA102. These candidates were compared with 11C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, 11C-IMA106 and 11C-IMA107 were taken into further evaluation and comparison with 11C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. Results: All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that 11C-IMA107 and 11C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of 11C-IMA107 and 11C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of 11C-IMA107 and 11C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. Conclusion: 11C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of 11C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that 11C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.

U2 - 10.2967/jnumed.113.131409

DO - 10.2967/jnumed.113.131409

M3 - Article

C2 - 24614221

SN - 1535-5667

VL - 55

SP - 595

EP - 601

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 4

ER -

Phosphodiesterase 10A PET radioligand development program: from pig to human

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