Molecular medicine offers promise for personalized cancer treatments with radiolabeled peptides and other macrocycles. New approaches in PET imaging for personalized diagnostics support this promise. Key to PET imaging is the ability to work with 18F, which gives higher resolution than 68Ga and is the only fully scalable PET-isotope. Yet its use for labeling peptides and other mid-size molecules has posed considerable challenges dominated by the chemical incompatiblity of anionic 18F-fluoride in aqueous conditions. To meet this challenge, we have developed a user-friendly one-step approach to 18F-labeling that is made possible by an organotrifluoroborate prosthetic group (or radiosynthon) that is pre-conjugated to the peptide to create a radiosynthetic precursor for kit-like labeling and automated radiofluorination. We have used this approach to advance numerous peptide radiotracers for unmet needs in cancer-specific imaging. Starting with up to 4 Ci (128 GBq), we achieve radiochemical yields range from 8-25% in &gt;95% radiochemical purity and at molar activities of 1-6 Ci/µmol (37-222 GBq/µmol) using simple isotope exchange in mildly acidic buffer. Depending on the peptide targeting agent, tumor uptake values typically range from 5-18% ID/g and tumor:muscle ratios can be as high as 100, with predominantly renal clearance and limited liver/intestinal accumulation owing to the very polar nature of the organotrifluoroborate prosthetic group. Most recently, we have applied this approach to label DOTA-peptides that now enable optionality in radioisotope choice for the creation of chemically equivalent but isotopically distinct tracers for iterative use in PET and radioligand therapy. The application of this novel method and its outcome to produce excellent preclinical PET images will be discussed.

Empowering PET imaging with one-step aqueous 18F-radiofluorination of peptides for theranostic development

ACS Spring 2022

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