A quinazoline-derivative DOTA-type gallium(III) complex for targeting epidermal growth factor receptors: synthesis, characterisation and biological studies

Abstract

The novel DOTA-like chelator 1,4,7,10-tetraazacyclododecane-1-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}propionamide-4,7,10-triacetic acid (H(3)L) was synthesised by alkylation of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(t-butyl acetate) with N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-bromopropionamide, followed by hydrolysis of the ester groups with trifluoracetic acid. H(3)L has been fully characterised by multinuclear NMR spectroscopy, mass spectrometry and high-performance liquid chromatography (HPLC). Five protonation constants, log K (Hi ), of H(3)L were determined by potentiometry and UV-vis spectrophotometry and the values found are 10.47, 9.18, 5.24, 4.00 and 2.23. These methods, complemented with variable-pH (71)Ga NMR studies, allowed us to ascertain the stability constant of the Ga(III) complex of L. GaL has a remarkably high thermodynamic stability constant (log K (ML) = 24.5). The radioactive complex (67)GaL was prepared in high yield and high radiochemical purity. Its HPLC chromatogram is identical to that obtained for the GaL complex prepared at the macroscopic level. At pH 7.4, (67)GaL has an overall neutral charge, is highly hydrophilic (log D = -1.02 +/- 0.03) and presents high in vitro stability in physiological media and in the presence of an excess of diethylenetriaminepentaethanoic acid . In vitro studies indicated that H(3)L and GaL do not inhibit the cell growth of epidermal growth factor receptor expressing cell lines, such as A431 cervical carcinoma cells, a result which agrees with the very low cell internalisation found for (67)GaL in the same cell line. Biodistribution studies in mice indicated high in vivo stability for (67)GaL, a high total excretion rate and a relatively slow blood clearance, in full accordance with its hydrophilic character and the relatively important protein binding.

NMR determination of free gallium(III) ions in aqueous solutions of Ga complexes, “cold” analogs of PET/SPECT tracers

“…In aqueous solution and depending on the pH, the Ga(III) ion can form different kinds of species, such as [Ga(H 2 O) 6 4 ] − can be observed by NMR, due to their highly symmetrical local environment of the gallium nucleus (11)(12) (Fig. 1 6 ] 3+ and its intensity raises gradually with the increase of pH value.…”

“…In spite of a lower natural abundance, 71 Ga is generally the preferred isotope because of its higher 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 (2,(11)(12)16), and C 3 -symmetric Ga-NOTA derivatives (17)(18)(19)(20)(21)(22). As a proof of concept, we have studied here a solution of the approximately octahedral complex Ga-DOTA.…”

Gallium compounds in nuclear medicine and oncology

“…There are also some conventional pharmaceuticals employing nonradio active Ga(III) pharmaceuticals used in oncology, e.g., Ga-EDTMP, for therapy of bone metastasis (Su et al, 2005); Ga(8-quinolinate)3, for treating renal cell cancer (Collery et al, 2000;Jalilian et al, 2005;Rudnev et al, 2006); Ga-semicarbazones, with a wide spectrum of antitumor effects in the ovary, breast, and colon (Rudnev et al, 2006;Kalinowski et al, 2009;Gambino et al, 2011); Ga(maltol)3, for the treatment of several types of cancer, including liver cancer and lymphoma (Rudnev et al, 2006); Ga(nitrate)3, for the treatment of lymphomas, bone metastasis, and bladder cancer (Collery et al, 2002;Jakupec and Keppler, 2004); Ga-porphyrins, a sonosensitizer in photodynamic therapy (Rosenthal et al, 2004;Jalilian et al, 2005); Gapyrazole and its derivatives, as antitumor agents for the therapy of ovarian adenocarcinoma and human lung carcinoma (Tajiri et al, 1994;Balbi et al, 2011); and Gathiolate ligands, for their dose-dependent antiproliferative effect toward cancer cells (Gallego et al, 2011). Besides low molecular weight ligands (Gallego et al, 2011;Collery et al, 2002;Rosenthal et al, 2004;Garcia et al, 2009), protein biopolymers and even whole cells have been successfully employed in Ga(III) pharmaceuticals, as illustrated in Table 2. The structure and properties of such protein ligands are further illustrated and mentioned in Table 3.…”

“…These are the radiopharmaceuticals employing radioactive 67,68 Ga(III) isotopes, e.g., Ga(imidazole)3 and its derivates, as epidermal growth factor receptors (Garcia et al, 2009); GaCl3, for imaging of lymphoma, inflammatory processes, transmitting nerve impulses, and regulatory fluid in and out of cells (Collery et al, 2000;Silvola et al, 2011); Ga-folate, as diagnostic agent for receptor-positive tumor (Melpomeni et al, 2011); Ga-citrate, suitable for scintigraphy for the detection of a wide variety of diseases: Hodgkin's, lung cancer, malignant lymphoma, and pancreatic cancer (Kunn et al, 1997;Liu et al, 2003;Lin et al, 2007); Ganitroimidazole and its derivative, for PET imaging of tumor hypoxia (Goldman, 1982;Juchau, 1989;Kunn et al, Brought to you by | University of Bath Authenticated Download Date | 6/13/15 1:16 AM 1997; Fernández et al, 2013); and Ga-biphosphonate, for PET tracing of bone lesions (Fellner et al, 2012). There are also some conventional pharmaceuticals employing nonradio active Ga(III) pharmaceuticals used in oncology, e.g., Ga-EDTMP, for therapy of bone metastasis (Su et al, 2005); Ga(8-quinolinate)3, for treating renal cell cancer (Collery et al, 2000;Jalilian et al, 2005;Rudnev et al, 2006); Ga-semicarbazones, with a wide spectrum of antitumor effects in the ovary, breast, and colon (Rudnev et al, 2006;Kalinowski et al, 2009;Gambino et al, 2011); Ga(maltol)3, for the treatment of several types of cancer, including liver cancer and lymphoma (Rudnev et al, 2006); Ga(nitrate)3, for the treatment of lymphomas, bone metastasis, and bladder cancer (Collery et al, 2002;Jakupec and Keppler, 2004); Ga-porphyrins, a sonosensitizer in photodynamic therapy (Rosenthal et al, 2004;Jalilian et al, 2005); Gapyrazole and its derivatives, as antitumor agents for the therapy of ovarian adenocarcinoma and human lung carcinoma (Tajiri et al, 1994;Balbi et al, 2011); and Gathiolate ligands, for their dose-dependent antiproliferative effect toward cancer cells (Gallego et al, 2011).…”

Applications of nuclear shielding

“…These methods, complemented with variable-pH 71 Ga NMR studies, allowed us to ascertain the stability constant of the Ga(III) complex, GaL. 217 2.13.4 Indium ( 115 In)(I = 9/2). Nuclear spin relaxation and the Knight shift for 71 Ga, 69 Ga and 115 In isotopes were studied by NMR (NMR) in liquid gallium-indium alloy confined to porous glass and alloy surface film and were compared with the bulk counterparts.…”