3-Cyano-4-[F]fluoro-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH

3-Cyano-4-[F]fluoro-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH, abbreviated as [F]6b, is a bombesin (BN)-based F-labeled peptide synthesized by Mu et al. for positron emission tomography (PET) of tumors expressing gastrin-releasing peptide receptor (GRPR) (1). BN is an amphibian neuropeptide consisting of 14 amino acids (pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH) (2, 3). The C-terminal region of BN is responsible for its receptor binding and signal transduction. BN and its mammalian counterpart, gastrin-releasing peptide (GRP), produce a wide range of biological responses in diverse tissues (3). They also act as growth factors for cancer cells. Of the BN receptors, GRPR (also known as BB or BRS2) is best characterized (2). GRPR is a glycosylated G-protein–coupled receptor and is normally expressed in non-neuroendocrine tissues of the breast and pancreas and in neuroendocrine cells of the brain, gastrointestinal tract, lung, and prostate (3, 4). Because GRPR is overexpressed in various tumors, a large number of BN analogs have been tested for GRPR-targeted imaging and therapy (5, 6). These analogs have been synthesized on the basis of either truncated BN (6–14 or 7–14) or full-length BN (1–14), and most analogs exhibit a high affinity to GRPR (7, 8). The truncated BN analogs appear more stable than the full-length tetradecapeptides, but the full-length peptides offer more labeling options by attachment of functional groups to the amino acids on positions 1 to 6 (6, 9). For most analogs, the amino acids on positions 13 (Leu) and 14 (Met) have been replaced with non-natural amino acids for increasing stability, and Lys has been placed on position 3 for attaching radiolabels (1, 10). Spacers, chelators, or radiometals have also been widely used for conjugation and for favorable kinetics (1, 11, 12). Functionally, most BN analogs act as agonists, and only a few to date are antagonists (9). Agonists are internalized into and accumulate within cells, and they have been assumed to exhibit higher uptake by cancer cells than antagonists. However, some studies have shown that tumor uptake of antagonists is higher than that of agonists because antagonists may have stronger binding for GRPR than agonists (9). Mu et al. synthesized a series of BN-based peptides by using different linkers, peptide sequences, and non-natural amino acids (1). These peptides have been labeled with F with a one-step approach F-for-N(CH) substitution using a less lipophilic benzonitrile labeling moiety. Amino acids such as His, Trp, Arg, and non-natural amino acids such as statine (Sta) and cysteine sulfonic acid (Ala(SOH)) in the peptide sequence did not require any protection group during radiosynthesis. Two analogs, one named as [F]6b and another [F]7b, exhibited specific uptake in GRPR-expressing PC-3 tumors and the pancreas in nude mice (1). [F]6b is positively charged, while [F]7b is negatively charged. This chapter describes the data obtained with [F]6b. The data obtained with [F]7b are described in the MICAD chapter on [F]7b.