The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin α v β 6 -Selective Peptide Labeled with Aluminum [ 18 F]Fluoride

• Published in: Molecular imaging and biology 2020-12, Vol.22 (6), p.1543
• Main Authors: Hausner, Sven H, Bauer, Nadine, Davis, Ryan A, Ganguly, Tanushree, Tang, Sarah Y C, Sutcliffe, Julie L
• Format: Article
• Language: English
• Subjects: Albumins - metabolism; Aluminum Compounds - chemistry; Animals; Antigens, Neoplasm - metabolism; Cell Line, Tumor; Female; Fluorides - chemistry; Fluorine Radioisotopes - chemistry; Integrins - metabolism; Mice, Nude; Peptides - chemistry; Peptides - pharmacokinetics; Positron Emission Tomography Computed Tomography; Protein Binding; Tissue Distribution
• ISSN: 1860-2002

The α β -BP peptide selectively targets the integrin α β , a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[ F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [ 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. The peptides NOTA-α β -BP (1) and NOTA-K(ABM)-α β -BP (2) were synthesized on solid phase, radiolabeled with aluminum [ F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [α β (+)]/DX3puro [α β (-)], and for [ F]AlF 2, BxPC-3 [α β (+)] cell xenografts (PET imaging, biodistribution). The peptides were radiolabeled in 23.0 ± 5.7 % and 22.1 ± 4.4 % decay-corrected radiochemical yield, respectively, for [ F]AlF 1 and [ F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin α β by ELISA (IC (α β ) = 3-7 nM vs IC (α β ) > 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 [ F]AlF 1 bound to human serum at 16.3 ± 1.9 %, compared to 67.5 ± 1.0 % for the ABM-containing [ F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1 % ID/g remaining in blood for [ F]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [ F]AlF 2 at 6 h p.i.) and higher α β (+) tumor uptake (4 h: DX3puroβ6; [ F]AlF 1: 3.0 ± 0.7 % ID/g, [ F]AlF 2: 7.2 ± 0.7 % ID/g; BxPC-3; [ F]AlF 2: 10.2 ± 0.1 % ID/g). Both compounds were prepared using standard chemistries; affinity and selectivity for integrin α β in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher α β -targeted uptake.