In Vivo Evaluation of 6 Analogs of 11 C-ER176 as Candidate 18 F-Labeled Radioligands for 18-kDa Translocator Protein.

Autor: Lee JH; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and jae-hoon.lee@nih.gov.; Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, South Korea., Siméon FG; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Liow JS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Morse CL; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Gladding RL; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Santamaria JAM; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Henter ID; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Zoghbi SS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Pike VW; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and., Innis RB; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
Jazyk: angličtina
Zdroj: Journal of nuclear medicine : official publication, Society of Nuclear Medicine [J Nucl Med] 2022 Aug; Vol. 63 (8), pp. 1252-1258. Date of Electronic Publication: 2022 Jan 13.
DOI: 10.2967/jnumed.121.263168
Abstrakt: Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand 11 C-ER176 can successfully image 18-kDa translocator protein (TSPO), a biomarker of inflammation, in the human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an 18 F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic 11 C labeling and in vivo performance in the monkey brain to select the most promising among 6 fluorine-containing analogs of ER176 for subsequent labeling with longer-lived 18 F. Methods: Six fluorine-containing analogs of ER176-3 fluoro and 3 trifluoromethyl isomers-were synthesized and labeled by 11 C methylation at the secondary amide group of the respective N -desmethyl precursor. PET imaging of the monkey brain was performed at baseline and after blockade by N -butan-2-yl-1-(2-chlorophenyl)- N -methylisoquinoline-3-carboxamide (PK11195). Uptake was quantified using radiometabolite-corrected arterial input function. The 6 candidate radioligands were ranked for performance on the basis of 2 in vivo criteria: the ratio of specific to nondisplaceable uptake (i.e., nondisplaceable binding potential [ BP ND ]) and the time stability of total distribution volume ( V T ), an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was quantified as V T corrected for plasma free fraction ( V T / f P ) using Logan graphical analysis for all 6 radioligands. V T / f P was generally high at baseline (222 ± 178 mL·cm -3 ) and decreased by 70%-90% after preblocking with PK11195. BP ND calculated using the Lassen plot was 9.6 ± 3.8; the o -fluoro radioligand exhibited the highest BP ND (12.1), followed by the m -trifluoromethyl (11.7) and m -fluoro (8.1) radioligands. For all 6 radioligands, V T reached 90% of the terminal 120-min values by 70 min and remained relatively stable thereafter, with excellent identifiability (SEs < 5%), suggesting that no significant radiometabolites accumulated in the brain. Conclusion: All 6 radioligands had good BP ND and good time stability of V T Among them, the o -fluoro, m -trifluoromethyl, and m -fluoro compounds were the 3 best candidates for development as radioligands with an 18 F label.
(© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)
Databáze: MEDLINE
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