RT Journal Article
SR Electronic
T1 In vivo evaluation of six analogs of <sup>11</sup>C-ER176 as candidate <sup>18</sup>F-labeled radioligands for translocator protein 18 kDa (TSPO)
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP jnumed.121.263168
DO 10.2967/jnumed.121.263168
A1 Jae-Hoon Lee
A1 Fabrice G. Simeon
A1 Jeih-San Liow
A1 Cheryl L. Morse
A1 Robert L. Gladding
A1 Jose Angel Montero Santamaria
A1 Ioline D. Henter
A1 Sami S. Zoghbi
A1 Victor W. Pike
A1 Robert B. Innis
YR 2022
UL http://jnm.snmjournals.org/content/early/2022/01/13/jnumed.121.263168.abstract
AB Due to its excellent ratio of specific to nondisplaceable uptake, the radioligand 11C-ER176 can successfully image 18kDa translocator protein (TSPO), a biomarker of inflammation, in human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an 18F-labeled TSPO positron emission tomography (PET) radioligand based on ER176 with the potential for broader distribution. This study used generic carbon-11 labeling and in vivo performance in monkey brain to select the most promising among six fluorine-containing analogs of ER176 for subsequent labeling with longer-lived fluorine-18. Methods: Six fluorine-containing analogs of ER176—three fluoro and three trifluoromethyl isomers—were synthesized and labeled by 11C-methylation at the secondary amide group of the respective N-desmethyl precursor. PET imaging was performed in monkey brain at baseline and after blockade by PK11195. . Uptake was quantified using radiometabolite-corrected arterial input function. The six candidate radioligands were ranked for performance based on two in vivo criteria: 1) ratio of specific to nondisplaceable uptake (BPND), and 2) time stability of total distribution volume (VT), an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was quantified as VT corrected for plasma free fraction (VT/fP) using Logan graphical analysis for all six radioligands. VT/fP at baseline was generally high (222±178 mL∙cm-3) and decreased by 70–90% after pre-blocking with PK11195. BPND calculated using the Lassen plot was 9.6±3.8; the o-fluoro radioligand exhibited the highest BPND of 12.1, followed by the m-trifluoromethyl (11.7) and m-fluoro (8.1) radioligands. For all six radioligands, VT values reached 90% of the terminal 120-minute values by 70 minutes and remained relatively stable thereafter with excellent identifiability (standard errors &lt; 5%), suggesting that no significant radiometabolites accumulated in the brain. Conclusion: All six radioligands had a good ratio of specific to nondisplaceable uptake (BPND) as well as good time stability of total receptor binding (VT). Among them, the o-fluoro, m-trifluoromethyl, and m-fluoro compounds were the three best candidates for development as radioligands with a fluorine-18 label.