The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin αvβ6-Selective Peptide Labeled with Aluminum [18F]Fluoride

Purpose The alpha(v)beta(6)-BP peptide selectively targets the integrin alpha(v)beta(6), a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[F-18]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [F-18]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life. Procedures The peptides NOTA-alpha(v)beta(6)-BP (1) and NOTA-K(ABM)-alpha(v)beta(6)-BP (2) were synthesized on solid phase, radiolabeled with aluminum [F-18]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puro beta 6 [alpha(v)beta(6)(+)]/DX3puro [alpha(v)beta(6)(-)], and for [F-18]AlF 2, BxPC-3 [alpha(v)beta(6)(+)] cell xenografts (PET imaging, biodistribution). Results The peptides were radiolabeled in 23.0 +/- 5.7 % and 22.1 +/- 4.4 % decay-corrected radiochemical yield, respectively, for [F-18]AlF 1 and [F-18]AlF 2. Both demonstrated excellent affinity and selectivity for integrin alpha(v)beta(6) by ELISA (IC50(alpha(v)beta(6)) = 3-7 nM vs IC50(alpha(v)beta(3)) > 10 mu M) and in cell binding studies (51.0 +/- 0.7 % and 47.2 +/- 0.7 % of total radioactivity bound to DX3puro beta 6 cells at 1 h, respectively, vs. <= 1.2 % to DX3puro for both compounds). The radiotracer [F-18]AlF 1 bound to human serum at 16.3 +/- 1.9 %, compared to 67.5 +/- 1.0 % for the ABM-containing [F-18]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (<= 0.1 % ID/g remaining in blood for [F-18]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [F-18]AlF 2 at 6 h p.i.) and higher alpha(v)beta(6)(+) tumor uptake (4 h: DX3puro beta 6; [F-18]AlF 1: 3.0 +/- 0.7 % ID/g, [F-18]AlF 2: 7.2 +/- 0.7 % ID/g; BxPC-3; [F-18]AlF 2: 10.2 +/- 0.1 % ID/g). Conclusion Both compounds were prepared using standard chemistries; affinity and selectivity for integrin alpha(v)beta(6) in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher alpha(v)beta(6)-targeted uptake.