Phosphodiesterase 10a pet radioligand development program: From pig to human

Christophe Plisson, David Plisson, 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

Research output: Contribution to journalArticle

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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 11CIMA107 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 languageEnglish
Pages (from-to)595-601
Number of pages7
JournalJournal of Nuclear Medicine
Volume55
Issue number4
DOIs
Publication statusPublished - Apr 1 2014

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Pets
Phosphoric Diester Hydrolases
Swine
Brain
Primates
Phosphodiesterase Inhibitors
Papio
IMA107
Cerebellum
Methylation
Outcome Assessment (Health Care)
Ligands

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Plisson, C., Plisson, D., Jakobsen, S., Natesan, S., Salinas, C., Lin, S. F., ... 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

Phosphodiesterase 10a pet radioligand development program : From pig to human. / Plisson, Christophe; Plisson, David; Jakobsen, Steen; Natesan, Sridhar; Salinas, Cristian; Lin, Shu Fei; Labaree, David; Zheng, Ming Qiang; Nabulsi, Nabeel; Marques, Tiago Reis; Kapur, Shitij; Kawanishi, Eiji; Saijo, Takeaki; Gunn, Roger N.; Carson, Richard E.; Rabiner, Eugenii A.

In: Journal of Nuclear Medicine, Vol. 55, No. 4, 01.04.2014, p. 595-601.

Research output: Contribution to journalArticle

Plisson, C, Plisson, D, Jakobsen, S, Natesan, S, Salinas, C, Lin, SF, Labaree, D, Zheng, MQ, 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
Plisson C, Plisson D, Jakobsen S, Natesan S, Salinas C, Lin SF et al. Phosphodiesterase 10a pet radioligand development program: From pig to human. Journal of Nuclear Medicine. 2014 Apr 1;55(4):595-601. https://doi.org/10.2967/jnumed.113.131409
Plisson, Christophe ; Plisson, David ; Jakobsen, Steen ; Natesan, Sridhar ; Salinas, Cristian ; Lin, Shu Fei ; Labaree, David ; Zheng, Ming Qiang ; Nabulsi, Nabeel ; Marques, Tiago Reis ; Kapur, Shitij ; Kawanishi, Eiji ; Saijo, Takeaki ; Gunn, Roger N. ; Carson, Richard E. ; Rabiner, Eugenii A. / Phosphodiesterase 10a pet radioligand development program : From pig to human. In: Journal of Nuclear Medicine. 2014 ; Vol. 55, No. 4. pp. 595-601.
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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 11CIMA107 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.",
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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.

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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 11CIMA107 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.

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