DATATOC: a novel conjugate for kit-type 68Ga labelling of TOC at ambient temperature
Tóm tắt
The widespread acceptance and application of 68Ga-PET depends on our ability to develop radiopharmaceuticals that can be prepared in a convenient and suitable manner. A kit-type labelling protocol provides such characteristics and requires chelators that can be radiolabelled under exceptionally mild conditions. Recently the DATA chelators have been introduced that fulfil these requirements. In continuing their development, the synthesis and radiolabelling of the first DATA bifunctional chelator (BFC) and peptide conjugate are described. A BFC derived from the DATA ligand (2,2’-(6-((carboxymethyl)amino)-1,4-diazepane-1,4-diyl)diacetic acid) has been synthesised in five steps from simple building blocks, with an overall yield of 8 %. DATAM5-3tBu (5-[1,4-Bis-tert-butoxycarbonylmethyl-6-(tert-butoxycarbonylmethyl-methyl-amino)-[1, 4]diazepan-6-yl]-pentanoic acid) has been coupled to [DPhe1][Tyr3]-octreotide (TOC) and the resulting peptide conjugate (DATATOC) radiolabelled with purified 68Ga derived via four different 68Ge/68Ga generator post-processing (PP) methods. The stability and lipophilicity of the radiotracer have been assessed and a kit-type formulation for radiolabelling evaluated. 68Ga-DATATOC has been prepared with a > 95 % radiochemical yield (RCY) within 1 (fractionated and acetone-PP) and 10 min (ethanol- and NaCl-PP) at 23 °C (pH 4.2–4.9, 13 nmol). The radiolabelled peptide is stable in the presence of human serum. Lipophilicity of 68Ga-DATATOC was calculated as logP = −3.2 ± 0.3, with a HPLC retention time (t
R = 10.4 min) similar to 68Ga-DOTATOC (logP = −2.9 ± 0.4, t
R = 10.3 min). Kit-type labelling from a lyophilised solid using acetone-PP based labelling achieves > 95 % RCY in 10 min at 23 °C. The favourable labelling properties of the DATA chelators have been retained for DATATOC. High radiochemical purity can be achieved at 23 °C in less than 1 min and from a kit formulation. The speed, reliability, ease, flexibility and simplicity with which 68Ga-DATATOC can be prepared makes it a very attractive alternative to current standards.
Tài liệu tham khảo
Asti M, Iori M, Capponi PC, Rubagotti S, Fraternali A, Versari A. Development of a simple kit-based method for preparation of pharmaceutical-grade 68Ga-DOTATOC. Nucl Med Commun. 2015;36:502–10.
Baranyai Z, Uggeri F, Giovenzana GB, Bényei A, Bruecher E, Aime S. Equilibrium and kinetic properties of the lanthanoids(III) and various divalent metal complexes of the heptadentate ligand AAZTA. Chem Eur J. 2009;15(7):1696–705.
Berry DJ, Ma Y, Ballinger JR, Tavaré R, Koers A, Sunassee K, et al. Efficient bifunctional 68Ga chelators for positron emission tomography: tris(hydroxypyridinone) ligands. Chem Commun. 2011;47(25):7068–70.
Boros E, Ferreira CL, Cawthray JF, Price EW, Patrick BO, Wester DW, et al. Acyclic chelate with ideal properties for 68Ga PET imaging agent elaboration. J Am Chem Soc. 2010;132(44):15726–33.
Boros E, Ferreira CL, Yapp DTT, Gill RK, Price EW, Adam MJ, et al. RGD conjugates of the H2dedpa scaffold: synthesis, labeling and imaging with 68Ga. Nucl Med Biol. 2012;39(6):785–94.
Breeman WAP, Jong M, Blois E, Bernard BF, Konijnenberg M, Krenning EP. Radiolabelling DOTA-peptides with 68Ga. Eur J Nucl Med Mol Imaging. 2005;32(4):478–85.
Buchmann I, Henze M, Engelbrecht S, Eisenhut M, Runz A, Schaefer M, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2007;34(10):1617–26.
Du CM, Valko K, Bevan C, Reynolds D, Abraham MH. Rapid Gradient RP-HPLC Method for Lipophilicity Determination: A Solvation Equation Based Comparison with Isocratic Methods. Anal Chem. 1998;70:4228–34.
Dumont RA, Deininger F, Haubner R, Maecke HR, Weber WA, Fani M. Novel 64Cu- and 68Ga-labeled RGD conjugates show improved PET imaging of ανβ3 integrin expression and facile radiosynthesis. J Nucl Med. 2011;52(8):1276–84.
Eder M, Waengler B, Knackmuss S, LeGall F, Little M, Haberkorn U, et al. Tetrafluorophenolate of HBED-CC: a versatile conjugation agent for 68Ga-labeled small recombinant antibodies. Eur J Nucl Med Mol Imaging. 2008;35(10):1878–86.
Eisenwiener K, Prata MIM, Buschmann I, Zhang H, Santos AC, Wenger S, et al. NODAGATOC, a New Chelator-Coupled Somatostatin Analogue Labeled with 67/68Ga and 111In for SPECT, PET, and Targeted Therapeutic Applications of Somatostatin Receptor (hsst2) Expressing Tumors. Bioconjugate Chem. 2002;13(3):530–41.
Eppard E, Wuttke M, Nicodemus PL, Roesch F. Ethanol-Based Post-processing of Generator-Derived 68Ga Toward Kit-Type Preparation of 68Ga-Radiopharmaceuticals. J Nucl Med. 2014;55(6):1023–8.
Fani M, André JP, Maecke HR. 68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals. Contrast Media Mol Imaging. 2008;3(2):67–77.
Fani M, Del Pozzo L, Abiraj K, Mansi R, Tamma ML, Cescato R, et al. PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. J Nucl Med. 2011;52(7):1110–8.
Fani M, Tamma M, Nicolas GP, Lasri E, Medina C, Raynal I, et al. In vivo imaging of folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugates. Mol Pharm. 2012;9(5):1136–45.
FDA Grants Orphan Drug Designation for 68Ga-DOTATOC. J Nucl Med. 2014;55(1):10 N.
Frilling A, Sotiropoulos GC, Radtke A, Malago M, Bockisch A, Kuehl H, et al. The impact of 68Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors. Ann Surg. 2010;252(5):850–6.
Lin M, Welch MJ, Lapi SE. Effects of chelator modifications on 68Ga-labeled [Tyr 3]octreotide conjugates. Mol Imaging Biol. 2013;15(5):606–13.
Manzoni L, Belvisi L, Arosio D, Bartolomeo MP, Bianchi A, Brioschi C, et al. Synthesis of Gd and 68Ga complexes in conjugation with a conformationally optimized RGD sequence as potential MRI and PET tumor-imaging probes. ChemMedChem. 2012;7(6):1084–93.
Mueller D, Klette I, Baum RP, Gottschaldt M, Schultz MK, Breeman WAP. Simplified NaCl based 68Ga concentration and labeling procedure for rapid synthesis of 68Ga radiopharmaceuticals in high radiochemical purity. Bioconjugate Chem. 2012;23(8):1712–7.
Mukherjee A, Pandey U, Chakravarty R, Sarma HD, Dash A. Single vial kit formulation for preparation of PET radiopharmaceutical: 68Ga-DOTA-TOC. J Radioanal Nucl Chem. 2014;302(3):1253–8.
Notni J, Šimeček J, Hermann P, Wester H. TRAP, a powerful and versatile framework for 68Ga radiopharmaceuticals. Chem Eur J. 2011;17(52):14718–22.
Notni J, Pohle K, Wester H. Be spoilt for choice with radiolabelled RGD peptides: preclinical evaluation of 68Ga-TRAP(RGD)3. Nucl Med Biol. 2013;40(1):33–41.
Ocak M, Antretter M, Knopp R, Kunkel F, Petrik M, Bergisadi N, et al. Full automation of 68Ga labelling of DOTA-peptides including cation exchange prepurification. Appl Radiat Isot. 2010;68(2):297–302.
Parker D, Waldron BP. Conformational analysis and synthetic approaches to polydentate perhydro-diazepine ligands for the complexation of gallium(III). Org Biomol Chem. 2013;11(17):2827–38.
Parker D, Waldron BP, Yufit DS. Crystallographic and solution NMR structural analyses of four hexacoordinated gallium(III) complexes based on ligands derived from 6-amino-perhydro-1,4-diazepine. Dalton Trans. 2013;42(22):8001–8.
Roesch F. Past, present and future of 68Ge/68Ga generators. Appl Radiat Isot. 2013;76:24–30.
Seemann J, Eppard E, Waldron BP, Ross TL, Roesch F. Cation exchange-based post-processing of 68Ga-eluate: A comparison of three solvent systems for labelling of DOTATOC, NO2APBP and DATAM. Appl Radiat Isot. 2015;98:54–9.
Seemann J, Waldron BP, Roesch F, Parker D. Approaching ‘kit-type’ labelling with 68Ga: the DATA chelators. Chem Med Chem. 2015;10:1019–26.
Simeček J, Zemek O, Hermann P, Wester H, Notni J. A monoreactive bifunctional triazacyclononane phosphinate chelator with high selectivity for 68Ga. ChemMedChem. 2012;7(8):1375–8.
Smith DL, Breeman WAP, Sims-Mourtada J. The untapped potential of 68Gallium-PET: the next wave of 68Ga-agents. Appl Radiat Isot. 2013;76:14–23.
Tran K, Khan S, Taghizadehasl M, Palazzo F, Frilling A, Todd JF, et al. 68Ga dotatate PET/CT is superior to other imaging modalities in the detection of medullary carcinoma of the thyroid in the presence of high serum calcitonin. Hell J Nucl Med. 2015;18:19–24.
Ugur O, Kothari PJ, Finn RD, Zanzonico P, Ruan S, Guenther I, et al. 66Ga labeled somatostatin analogue DOTA-DPhe-Tyr-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors. Nucl Med Biol. 2002;29:147–57.
Velikyan I, Maecke H, Langstrom B. Convenient preparation of 68Ga-based PET-radiopharmaceuticals at room temperature. Bioconjug. Chem. 2008;19(2):567–73.
Virgolini I, Ambrosini V, Bomanji JB, Baum RP, Fanti S, Gabriel M, et al. Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging. 2010;37(10):2004–10.
Waengler C, Waengler B, Lehner S, Elsner A, Todica A, Bartenstein P, et al. A universally applicable 68Ga-labeling technique for proteins. J Nucl Med. 2011;52(4):586–91.
Waldron BP, Parker D, Burchardt C, Yufit DS, Zimny M, Roesch F. Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with 68Ga. Chem Commun. 2013;49(6):579–81.
Wester H, Brockmann J, Roesch F, Wutz W, Herzog H, Smith-Jones P, et al. PET-pharmacokinetics of 18F-octreotide: A comparison with 67Ga-DFO and 86Y-DTPA-octreotide. Nucl Med Biol. 1997;24(4):275–86.
Zhernosekov KP, Filosofov DV, Baum RP, Aschoff P, Bihl H, Razbash AA, et al. Processing of generator-produced 68Ga for medical application. J Nucl Med. 2007;48(10):1741–8.