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

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 ¹⁸F-labeled FR-targeted positron emission tomography (PET) tracer [¹⁸F]AlF-NOTA-Asp₂-PEG₂-Folate modified with a hydrophilic linker (-Asp₂-PEG₂) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [¹⁸F]AlF-NOTA-Asp₂-PEG₂-Folate was manually synthesized within 30 min with a non-decay-corrected radiochemical yield of 16.3 ± 2.0% (n = 5). Among KB cells, [¹⁸F]AlF-NOTA-Asp₂-PEG₂-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 [¹⁸F]AlF-NOTA-Asp₂-PEG₂-Folate, compared to the known tracer [¹⁸F]AlF-NOTA-Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [¹⁸F]AlF-NOTA-Asp₂-PEG₂-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.