UCLA

Background

Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for ¹⁸F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([¹⁸F]AMBF₃-TATE), a promising ¹⁸F-labeled analog that could compete with [⁶⁸Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced.

Methods

Both [¹⁸F]AMBF₃-TATE and [⁶⁸Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [¹⁸F]AMBF₃-TATE.

Results

The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [¹⁸F]AMBF₃-TATE in SSTR2 tumor models correlated well with [⁶⁸Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10^-2 mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical ¹⁸F- and ⁶⁸Ga-labeled compounds.

Conclusions

The combination of novel chemical approaches to ¹⁸F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of ¹⁸F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [¹⁸F]AMBF₃-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.