Synthesis and Preclinical Evaluation of [18F]AlF‐NOTA‐Asp2‐PEG2‐Folate as a Novel Folate‐Receptor‐Targeted Tracer for PET Imaging

ABSTRACT Recently, the folate receptor (FR) has become an exciting target for the diagnosis of FR‐positive malignancies. Nevertheless, suboptimal in vivo pharmacokinetic properties, particularly high uptake in the renal and hepatobiliary systems, are important limiting factors for the clinical translation of most FR‐based radiotracers. In this study, we developed a novel 18 F‐labeled FR‐targeted positron emission tomography (PET) tracer [ 18 F]AlF‐NOTA‐Asp 2 ‐PEG 2 ‐Folate modified with a hydrophilic linker (−Asp 2 ‐PEG 2 ) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [ 18 F]AlF‐NOTA‐Asp 2 ‐PEG 2 ‐Folate was manually synthesized within 30 min with a non‐decay‐corrected radiochemical yield of 16.3 ± 2.0% ( n = 5). Among KB cells, [ 18 F]AlF‐NOTA‐Asp 2 ‐PEG 2 ‐Folate exhibited high specificity and affinity for FR. PET/CT imaging and biodistribution experiments in KB tumor‐bearing mice showed decent tumor uptake (1.7 ± 0.3% ID/g) and significantly decreased uptake in kidneys and liver (22.2 ± 2.1 and 0.3 ± 0.1% ID/g at 60 min p.i., respectively) of [ 18 F]AlF‐NOTA‐Asp 2 ‐PEG 2 ‐Folate, compared to the known tracer [ 18 F]AlF‐NOTA‐Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [ 18 F]AlF‐NOTA‐Asp 2 ‐PEG 2 ‐Folate, including its efficient synthesis, decent tumor uptake, relatively low renal uptake, and rapid clearance from most normal organs, portray it as a promising PET tracer for FR‐positive tumors.