Dopamine D1 Receptor Agonist PET Tracer Development: Assessment in Nonhuman Primates

被引：2

作者：

Barret, Olivier ^{[1
,2
]}

Zhang, Lei ^{[3
]}

Alagille, David ^{[1
,4
]}

Constantinescu, Cristian C. ^{[1
]}

Sandiego, Christine ^{[1
]}

Papin, Caroline ^{[1
]}

Sullivan, Jenna M. ^{[1
]}

Morley, Thomas ^{[1
]}

Carroll, Vincent M. ^{[1
]}

Seibyl, John ^{[1
]}

Chen, Jianqing ^{[5
]}

Lee, Chewah ^{[3
]}

Villalobos, Anabella ^{[3
]}

Gray, David ^{[3
,6
]}

McCarthy, Timothy J. ^{[5
]}

Tamagnan, Gilles ^{[1
,4
]}

机构：

[1] Invicro LLC, New Haven, CT 06510 USA

[2] Univ Paris Saclay, Lab Malad Neurodegenerat, CEA, CNRS,MIRCen, Fontenay Aux Roses, France

[3] Pfizer Inc, Med Design, Med Chem, Cambridge, MA USA

[4] Xing Imaging, New Haven, CT USA

[5] Pfizer Inc, Early Clin Dev, Digital Med & Imaging, Cambridge, MA USA

[6] Cerevel Therapeut, Boston, MA USA

来源：

JOURNAL OF NUCLEAR MEDICINE | 2021年 / 62卷 / 09期

基金：

美国国家卫生研究院;

关键词：

D-1; receptor; agonist; PET imaging; schizophrenia; Parkin-son disease; IN-VIVO; BINDING; DIHYDREXIDINE; D-1-DOPAMINE; RADIOTRACER; SELECTIVITY; PARAMETERS;

D O I：

10.2967/jnumed.120.256008

中图分类号：

R8 [特种医学]; R445 [影像诊断学];

学科分类号：

1002 ; 100207 ; 1009 ;

摘要：

Non-catechol-based high-affinity selective dopamine D-1 receptor (D1R) agonists were recently described, and candidate PET ligands were selected on the basis of favorable properties. The objective of this study was to characterize in vivo in nonhuman primates 2 novel D1R agonist PET radiotracers, racemic F-18-MNI-800 and its more active atropisomeric (-)-enantiomer, F-18-MNI-968. Methods: Ten brain PET experiments were conducted with F-18-MNI-800 on 2 adult rhesus macaques and 2 adult cynomolgus macaques, and 8 brain PET experiments were conducted with F-18-MNI-968 on 2 adult rhesus macaques and 2 adult cynomolgus macaques. PET data were analyzed with both plasma-input-based methods and reference-region-based methods. Whole-body PET images were acquired with F-18-MNI-800 from 2 adult rhesus macaques for radiation dosimetry estimates. Results: F-18-MNI-800 and F-18-MNI-968 exhibited regional uptake consistent with D1R distribution. Specificity and selectivity were demonstrated by dose-dependent blocking with the D-1 antagonist SCH-23390. F-18-MNI-968 showed a 30% higher specific signal than F-18-MNI-800, with a nondisplaceable binding potential of approximately 0.3 in the cortex and approximately 1.1 in the striatum. Dosimetry radiation exposure was favorable, with an effective dose of about 0.023 mSv/MBq. Conclusion: F-18-MNI-968 has significant potential as a D1R agonist PET radiotracer, and further characterization in human subjects is warranted.

引用

页码：1307 / 1313

页数：7

共 29 条

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