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

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PURPOSE: The α v β 6 -BP peptide selectively targets the integrin α v β 6, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[ 18 F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [ 18 F]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-α v β 6 -BP (1) and NOTA-K(ABM)-α v β 6 -BP (2) were synthesized on solid phase, radiolabeled with aluminum [ 18 F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [α v β 6 (+)]/DX3puro [α v β 6 (-)], and for [ 18 F]AlF 2, BxPC-3 [α v β 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 [ 18 F]AlF 1 and [ 18 F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin α v β 6 by ELISA (IC 50 (α v β 6 ) = 3-7 nM vs IC 50 (α v β 3 ) > 10 μM) and in cell binding studies (51.0 ± 0.7 % and 47.2 ± 0.7 % of total radioactivity bound to DX3puroβ6 cells at 1 h, respectively, vs. ≤ 1.2 % to DX3puro for both compounds). The radiotracer [ 18 F]AlF 1 bound to human serum at 16.3 ± 1.9 %, compared to 67.5 ± 1.0 % for the ABM-containing [ 18 F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1 % ID/g remaining in blood for [ 18 F]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [ 18 F]AlF 2 at 6 h p.i.) and higher α v β 6 (+) tumor uptake (4 h: DX3puroβ6; [ 18 F]AlF 1: 3.0 ± 0.7 % ID/g, [ 18 F]AlF 2: 7.2 ± 0.7 % ID/g; BxPC-3; [ 18 F]AlF 2: 10.2 ± 0.1 % ID/g).

CONCLUSION: Both compounds were prepared using standard chemistries; affinity and selectivity for integrin α v β 6 in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher α v β 6 -targeted uptake.