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

• Published in: Molecular imaging and biology 2020-12, Vol.22 (6), p.1543-1552
• Main Authors: Hausner, Sven H., Bauer, Nadine, Davis, Ryan A., Ganguly, Tanushree, Tang, Sarah Y. C., Sutcliffe, Julie L.
• Format: Article
• Language: English
• Subjects: Affinity; Albumin; Albumins; Aluminum; Animal models; Binding; Blood circulation; Cell surface; Chelation; Fluorides; Fluorine isotopes; Half-life; Imaging; In vivo methods and tests; Medicine; Medicine & Public Health; Peptides; Pharmacokinetics; Pharmacology; Positron emission; Radioactive half-life; Radioactive tracers; Radioactivity; Radiochemistry; Radiolabelling; Radiology; Research Article; Selectivity; Solid phases; Tomography; Xenografts; Xenotransplantation
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-020-01500-0

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.