AUTHOR=Lin Liping , Xiang Xianhong , Su Shu , Liu Shaoyu , Xiong Ying , Ma Hui , Yuan Gongjun , Nie Dahong , Tang Ganghua 

TITLE=Biological Evaluation of [18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.630452

DOI=10.3389/fchem.2021.630452

ISSN=2296-2646

ABSTRACT=<p><bold>Purpose:</bold> N-(2-[<sup>18</sup>F]fluoropropionyl)-L-glutamate ([<sup>18</sup>F]FPGLU) for hepatocellular carcinoma (HCC) imaging has been performed in our previous studies, but its radiosynthesis method and stability <italic>in vivo</italic> need to be improved. Hence, we evaluated the synthesis and biological properties of a simple [<sup>18</sup>F]-labeled glutamate analog, [<sup>18</sup>F]AlF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl)-l-glutamate ([<sup>18</sup>F]AlF-NOTA-NSC-GLU), for HCC imaging.</p><p><bold>Procedures:</bold> [<sup>18</sup>F]AlF-NOTA-NSC-GLU was synthesized via a one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [<sup>18</sup>F]AlF-NOTA-NSC-GLU in HCC, we conducted positron emission tomography/computed tomography (PET/CT) imaging and competitive binding of [<sup>18</sup>F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [<sup>18</sup>F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments <italic>in vitro</italic>.</p><p><bold>Results:</bold> [<sup>18</sup>F]AlF-NOTA-NSC-GLU was prepared with an overall radiochemical yield of 29.3 ± 5.6% (<italic>n</italic> = 10) without decay correction within 20 min. <italic>In vitro</italic> competitive inhibition experiments demonstrated that the Na<sup>+</sup>-dependent systems <inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>X</mml:mtext></mml:mrow><mml:mrow><mml:mtext>AG</mml:mtext></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula>, B0<sup>+</sup>, ASC, and minor <inline-formula><mml:math id="M2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>X</mml:mtext></mml:mrow><mml:mrow><mml:mtext>C</mml:mtext></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula> were involved in the uptake of [<sup>18</sup>F]AlF-NOTA-NSC-GLU, with the Na<sup>+</sup>-dependent system <inline-formula><mml:math id="M3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>X</mml:mtext></mml:mrow><mml:mrow><mml:mtext>AG</mml:mtext></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula> possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line showed almost no protein incorporation. Micro-PET/CT imaging with [<sup>18</sup>F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [<sup>18</sup>F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [<sup>18</sup>F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. <italic>In vivo</italic> competitive binding experiments showed that the tumor-to-liver uptake ratio decreased with the addition of inhibitors to block the X<sub>AG</sub> system.</p><p><bold>Conclusions:</bold> We have successfully synthesized [<sup>18</sup>F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [<sup>18</sup>F]AlF-NOTA-NSC-GLU may be a potential candidate for HCC imaging. Also, a further biological evaluation is underway.</p>