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 F-18-labeled FR-targeted positron emission tomography (PET) tracer [F-18]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 [F-18]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, [F-18]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 [F-18]AlF-NOTA-Asp(2)-PEG(2)-Folate, compared to the known tracer [F-18]AlF-NOTA-Folate (78.6 +/- 5.1 and 5.3 +/- 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [F-18]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.