HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Poethko, T. Articles by Wester, H.-J. Search for Related Content PubMed PubMed Citation Articles by Poethko, T. Articles by Wester, H.-J.

Two-Step Methodology for High-Yield Routine Radiohalogenation of Peptides: ¹⁸F-Labeled RGD and Octreotide Analogs

¹ Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
² Institut für Organische Chemie und Biochemie, Technische Universität München, München, Germany

Routine application of ¹⁸F-labeled peptides for quantitative in vivo receptor imaging of receptor-expressing tissues and quantification of receptor status using PET is limited by the lack of appropriate radiofluorination methods for routine large-scale synthesis of ¹⁸F-labeled peptides. To satisfy this demand, a new ¹⁸F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and an ¹⁸F-labeled aldehyde or ketone was investigated and optimized with respect to peptide conjugation. Methods: 4-[¹⁸F]Fluorobenzaldehyde ([¹⁸F]FB-CHO) was prepared from the 4-formyl-N,N,N-trimethylanilinium precursor via direct no-carrier-added ¹⁸F-fluorination (dimethyl sulfoxide, 60°C, 15 min) and purified using a cation-exchange/reversed-phase cartridge system. Radiochemical yields (RCYs) of N-(4-[¹⁸F]fluorobenzylidene)oxime ([¹⁸F]FBOA) formation with various aminooxy-modified peptides such as minigastrin, RGD, and octreotate analogs were investigated as a function of reaction time and temperature, peptide concentration, and pH. Biodistribution studies were performed with an [¹⁸F]FBOA-RGD dimer ((c(RGDfE)HEG)₂-K-Dpr-[¹⁸F]FBOA, 60 and 120 min after injection) and a gylcosylated [¹⁸F]FB-Tyr³-octreotate (Gluc-S-Dpr([¹⁸F]FBOA)TOCA), 10 and 60 min after injection) using M21 and M21L human melanoma and AR42J rat pancreatic tumor-bearing nude mice, respectively. Results: [¹⁸F]FB-CHO was obtained in a nonoptimized RCY of 50% within 30 min. At low peptide concentrations (0.5 mmol/L), optimal [¹⁸F]FBOA-labeling efficiencies (60%–80%) were obtained within 15 min at 60°C and pH 2–3, independently of the peptide used, affording the [¹⁸F]FBOA-peptides in overall RCYs of up to 40% (from end of bombardment) after purification. Both (c(RGDfE)HEG)₂-K-Dpr-[¹⁸F]FBOA and Gluc-S-Dpr([¹⁸F]FBOA)TOCA showed pharmacokinetics suitable for early (60 min) high-contrast PET imaging, high tumor uptake (2.48 ± 0.15 %ID/g [RGD] and 21.8 ± 1.4 %ID/g [TOCA] at 60 min after injection, where %ID/g = percentage injected dose per gram), and tumor-to-organ ratios that compared well with the corresponding [¹⁸F]fluoropropionyl analogs [¹⁸F] Galacto-RGD and Gluc-Lys([¹⁸F]FP)TOCA, which are prepared via multistep procedures. Conclusion: Oxime formation between aminooxy-functionalized peptides and an ¹⁸F-labeled aldehyde or ketone—in this case, [¹⁸F]FB-CHO—combines fast 1-step, high-yield synthesis of an ¹⁸F-labeled prosthetic group stable against in vivo defluorination with rapid, 1-step chemoselective conjugation to unprotected peptides under mild conditions. Thus, it allows fast and straightforward large-scale production of ¹⁸F-labeled peptides for clinical routine PET application. Furthermore, it opens new perspectives to peptide radiohalogenation in general, permitting labeling of the same precursor both with diagnostic (¹⁸F, ¹²⁴I, ^120gI, ¹²³I) and therapeutic (²¹¹At, ¹³¹I) radiohalogens.

Key Words: peptides • radiohalogenation • ¹⁸F • PET

This article has been cited by other articles:

				D. A. Harki, N. Satyamurthy, D. B. Stout, M. E. Phelps, and P. B. Dervan In vivo imaging of pyrrole-imidazole polyamides with positron emission tomography PNAS, September 2, 2008; 105(35): 13039 - 13044. [Abstract] [Full Text] [PDF]

				Z. Cheng, O. P. De Jesus, M. Namavari, A. De, J. Levi, J. M. Webster, R. Zhang, B. Lee, F. A. Syud, and S. S. Gambhir Small-Animal PET Imaging of Human Epidermal Growth Factor Receptor Type 2 Expression with Site-Specific 18F-Labeled Protein Scaffold Molecules J. Nucl. Med., May 1, 2008; 49(5): 804 - 813. [Abstract] [Full Text] [PDF]

				J. M. Jeong, M. K. Hong, Y. S. Chang, Y.-S. Lee, Y. J. Kim, G. J. Cheon, D. S. Lee, J.-K. Chung, and M. C. Lee Preparation of a Promising Angiogenesis PET Imaging Agent: 68Ga-Labeled c(RGDyK)-Isothiocyanatobenzyl-1,4,7-Triazacyclononane-1,4,7-Triacetic Acid and Feasibility Studies in Mice J. Nucl. Med., May 1, 2008; 49(5): 830 - 836. [Abstract] [Full Text] [PDF]

				Z.-B. Li, Z. Wu, K. Chen, E. K. Ryu, and X. Chen 18F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging J. Nucl. Med., March 1, 2008; 49(3): 453 - 461. [Abstract] [Full Text] [PDF]

				Z. Wu, Z.-B. Li, K. Chen, W. Cai, L. He, F. T. Chin, F. Li, and X. Chen microPET of Tumor Integrin {alpha}v{beta}3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4) J. Nucl. Med., September 1, 2007; 48(9): 1536 - 1544. [Abstract] [Full Text] [PDF]

				S. H. Hausner, D. DiCara, J. Marik, J. F. Marshall, and J. L. Sutcliffe Use of a Peptide Derived from Foot-and-Mouth Disease Virus for the Noninvasive Imaging of Human Cancer: Generation and Evaluation of 4-[18F]Fluorobenzoyl A20FMDV2 for In vivo Imaging of Integrin {alpha}v{beta}6 Expression with Positron Emission Tomography Cancer Res., August 15, 2007; 67(16): 7833 - 7840. [Abstract] [Full Text] [PDF]

				H.-J. Wester Nuclear Imaging Probes: from Bench to Bedside Clin. Cancer Res., June 15, 2007; 13(12): 3470 - 3481. [Abstract] [Full Text] [PDF]

				W. Cai, X. Zhang, Y. Wu, and X. Chen A Thiol-Reactive 18F-Labeling Agent, N-[2-(4-18F-Fluorobenzamido)Ethyl]Maleimide, and Synthesis of RGD Peptide-Based Tracer for PET Imaging of {alpha}v{beta}3 Integrin Expression J. Nucl. Med., July 1, 2006; 47(7): 1172 - 1180. [Abstract] [Full Text] [PDF]

				H.-J. Wester and H. Kessler Molecular Targeting with Peptides or Peptide-Polymer Conjugates: Just a Question of Size? J. Nucl. Med., December 1, 2005; 46(12): 1940 - 1945. [Full Text] [PDF]

				G. J. Kelloff, K. A. Krohn, S. M. Larson, R. Weissleder, D. A. Mankoff, J. M. Hoffman, J. M. Link, K. Z. Guyton, W. C. Eckelman, H. I. Scher, et al. The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development Clin. Cancer Res., November 15, 2005; 11(22): 7967 - 7985. [Abstract] [Full Text] [PDF]

				B. R. Line, A. Mitra, A. Nan, and H. Ghandehari Targeting Tumor Angiogenesis: Comparison of Peptide and Polymer-Peptide Conjugates J. Nucl. Med., September 1, 2005; 46(9): 1552 - 1560. [Abstract] [Full Text] [PDF]