Folate-PEG-NOTA-Al[18F], an improved PET agent for imaging folate receptor-positive tumors

Objectives Folate receptor (FR) has been identified as an important target for cancer therapy. A successful clinical FR targeting PET agent would facilitate the identification of small FR positive lesions and reduce scan time, which are key advantages over [99mTc]-EC20 SPECT clinical imaging. In this study, we designed and evaluated a new folate-PET agent, folate-PEG12-NOTA-Al[18F], and compared it to another folate targeting PET tracer folate-NOTA-Al[18F].

Methods Folate-PEG12-NOTA-Al[18F] synthesis was accomplished via one-pot labeling procedure by heating folate-PEG12-NOTA with in situ prepared ([18F]AlF)2+ for 15 min at 105 °C, followed by HPLC purification. Female 6-8 week-old nu/nu mice were implanted with KB (high FR expressors), Cal51 and A549 (low FR expressors) cell xenografts. Specific binding of the radiotracer to the FR was evaluated in homogenates of KB and Cal51 tumor xenografts, with in vivo imaging performed in mice bearing either KB or A549 tumor xenografts. Specific uptake of the radiotracer in tumor and other tissues was evaluated by micro-PET imaging and ex vivo biodistribution in the presence and absence of excess folic acid (FA).

Results Total radiochemical synthesis including radioactive HPLC purification of folate-PEG12-NOTA-Al[18F] was completed within 35 min, affording pure radiotracer in ~ 25-30% radiochemical yield with ~ 100% radiochemical purity and a specific activity of 1320 ± 460 Ci/mmol. Analysis of FR binding revealed Kd of 0.4 nM and 1.2 nM, and binding potential (Bmax / Kd) of 603 and 11 in KB and Cal51 xenografts, respectively. Uptake of folate-PEG12-NOTA-Al[18F] was higher in KB xenografts (2.33 ± 0.13 SUV) compared to A549 (0.53 ± 0.06 SUV), and the uptake could be blocked by FA. Folate-PEG12-NOTA-Al[18F] showed higher FR-mediated uptake in FR positive tumor and reduced accumulation in liver compared to folate-NOTA-Al[18F].

Conclusions Folate-PEG12-NOTA-Al[18F] synthesis was achieved through one-step radiolabeling strategy which is efficient and reproducible. The tracer demonstrated higher specific binding to the FR positive tumor and improved biodistribution compared to folate-NOTA-Al[18F]. There is potential for further development of folate-PEG12-NOTA-Al[18F] as a PET imaging agent and diagnostic tool targeting FR positive tumors for clinical study.