In vitro and in vivo evaluation of the effects of aluminum [18 F]fluoride radiolabeling on an integrin αv β6 -specific peptide

• Published in: Nuclear medicine and biology 2014, Vol.41 (1), p.43-50
• Main Authors: Hausner, Sven H, Bauer, Nadine, Sutcliffe, Julie L
• Format: Article
• Language: English
• Subjects: Aluminum - chemistry; Aluminum [18F]fluoride; Animals; Antigens, Neoplasm - metabolism; Benzoates - chemistry; Cell Line, Tumor; Drug Stability; Female; Fluorine 18; Fluorine Radioisotopes; Heterocyclic Compounds - chemistry; Integrin; Integrins - metabolism; Isotope Labeling - methods; Mice; NOTA; Peptide; Peptides - blood; Peptides - metabolism; Peptides - pharmacokinetics; Positron emission tomography; Radiology; Substrate Specificity
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2013.09.009

Abstract Introduction Incorporation of fluorine-18 (18 F) into radiotracers by capturing ionic [18 F]-species can greatly accelerate and simplify radiolabeling for this important positron emission tomography (PET) radioisotope. Among the different strategies, the incorporation of aluminum [18 F]fluoride (Al[18 F] 2 + ) into NOTA chelators has recently emerged as a robust approach to peptide radiolabeling. This study presents Al[18 F] 2 + -radiolabeling of an αv β6 integrin-targeted peptide (NOTA-PEG28 -A20FMDV2) and its in vitro and in vivo evaluation. Methods Aluminum [18 F]fluoride was prepared at r.t. from [18 F]fluoride (40 MBq–11 GBq) and introduced into NOTA-PEG28 -A20FMDV2 ( 1 ) in sodium acetate (pH 4.1; 100°C, 15 min). The radiotracer Al[18 F] NOTA-PEG28 -A20FMDV2 ( 2 ) was purified by HPLC, formulated in PBS and evaluated in vitro (stability; binding and internalization in αv β6 (+) and αv β6 (−) cells) and in vivo (paired αv β6 (+) and αv β6 (−) xenograft mice: PET/CT, biodistribution, tumor autoradiography and metabolites). Results The radiotracer 2 was prepared in 90 ± 6 min (incl. formulation; n = 3) in 19.3 ± 5.4% decay corrected radiochemical yield (radiochemical purity: > 99%; specific activity: 158 ± 36 GBq/μmol) and was stable in PBS and serum (2 h). During in vitro cell binding studies, 2 showed high, αv β6 -targeted binding (αv β6 (+): 42.4 ± 1.2% of total radioactivity, ratio (+)/(−) = 8.4/1) and internalization (αv β6 (+): 28.3 ± 0.5% of total radioactivity, (+)/(−) = 11.7/1). In vivo, 2 maintained αv β6 -targeted binding (biodistribution; 1 h: αv β6 (+): 1.74 ± 0.38% ID/g, (+)/(−) = 2.72/1; 4 h: αv β6 (+): 1.21 ± 0.56% ID/g, (+)/(−) = 4.0/1; 11% intact 2 in tumor at 1 h), with highest uptake around the tumor edge (autoradiography). Most of the radioactivity cleared rapidly in the urine within one hour, but a significant fraction remained trapped in the kidneys (4 h: 229 ± 44% ID/g). Conclusion The Al[18 F]/NOTA-based radiolabeling was rapid and efficient, and the radiotracer 2 showed good αv β6 -selectivity in vitro and in vivo. However, in contrast to A20FMDV2 labeled with covalently bound [18 F]-prosthetic groups (e.g., [18 F]fluorobenzoic acid), 2 demonstrated significant trapping in kidneys, similar to radiometal-labeled chelator-analogs of 2.