Purpose AAZTA (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) based chelators were initially developed in the context of magnetic resonance imaging. First radiochemical studies showed the capability of AAZTA to form stable complexes with radiolanthanides and moderately stable complexes with 68 Ga. For a systematic comparison of the labelling capabilities with current diagnostic and therapeutic trivalent radiometals, AAZTA 5 (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine) was synthesized representing a bifunctional version with a pentanoic acid at the carbon-6 atom. To evaluate the effect of adding a targeting vector (TV) to the bifunctional chelator on the complex formation, AAZTA 5 -TOC was synthesized, radiolabeled and tested in comparison to the uncoupled AAZTA 5 . Methods AAZTA 5 was synthesized in a 5-step synthesis. It was coupled to the cyclic peptide TOC (Phe 1 -Tyr 3 octreotide) via amide bound formation. AAZTA and AAZTA 5 -TOC complex formations with 68 Ga, 44 Sc and 177 Lu were investigated at different pH, temperature and precursor amounts. Stability studies against human serum, PBS buffer, EDTA and DTPA were performed. Results AAZTA 5 and AAZTA 5 -TOC achieved quantitative labelling (> 95%) at room temperature in less than 5 min with all three nuclides at pH ranges from 4 to 5.5 with low precursor amounts of 1 to 10 nmol. [ 44 Sc]Sc-AAZTA 5 complexes as well as [ 44 Sc]Sc-AAZTA 5 -TOC were completely stable. The 177 Lu complexes of AAZTA 5 and AAZTA 5 -TOC showed high stability comparable to the 44 Sc complexes. In contrast, the [ 68 Ga]Ga-AAZTA 5 complex stability was rather low, but interestingly, [ 68 Ga]Ga-AAZTA 5 -TOC was completely stable. Conclusion AAZTA 5 appears to be a promising bifunctional chelator for 68 Ga, 44 Sc and 177 Lu with outstanding labelling capabilities at room temperature. Complex stabilities are high in the case of 44 Sc and 177 Lu. While [ 68 Ga]Ga-AAZTA complexes alone lacking stability, [ 68 Ga]Ga-AAZTA ...

Abstract:The development of 68 Ge/ 68 Ga generators has made the positron emitting 68 Ga isotope widely accessible, raising interest in new chelate complexes of Ga 3+ . ). The stability constants of Ga(DATA m ) and Ga(DATA 5m ) complexes are slightly higher than those of the Ga(AAZTA). The species distribution calculations indicate the predominance of Ga(L)OH mixed hydroxo complexes at physiological pH. The 1 H-and 71 Ga-NMR studies provided information about the coordinated functional groups of ligands and on the kinetics of exchange between the Ga(L) and Ga(L)OH complexes. The transmetallation reactions between the Ga(L) complexes and Cu 2+ -citrate (6

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Purpose The widespread use of 68 Ga for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to 68 Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr 3 ]octreotide (TOC), a somatostatin subtype 2 receptor (SST 2 )-targeting vector for imaging and functional characterisation of SSTR 2 expressing tumours. Methods The radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex nat Ga(III) and 68 Ga(III). Competition binding assays of [ nat Ga]Ga-DATA-TOC or [ nat Ga]Ga-DOTA-TOC against [ 125 I-Tyr 25 ]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST 2,3,5 receptor subtypes (HEK293-hSST 2/3/5 cells). First in vivo studies were performed in female NMRI-nude mice bearing SST 2 -positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST 2 -specific tumour-targeting of [ 68 Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [ 68 Ga]Ga-DOTA-TOC reference. A direct comparison of [ 68 Ga]Ga-DATA-TOC with the well-established PET radiotracer [ 68 Ga]Ga-DOTA-TOC was additionally performed in a 46-year-old male patient with a well-differentiated NET (neuroendocrine tumour), representing the first in human administration of [ 68 Ga]Ga-DATA-TOC. Results DATA-TOC was labelled with 68 Ga with a radiolabelling efficiency of > 95% in less than 10 min at ambient temperature. A molar activity up to 35 MBq/nmol was achieved. The hSST 2 -affinities of [ nat Ga]Ga-DATA-TOC and [ nat Ga]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC 50 values. In mice, [ 68 Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [ 68 Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two 68 Ga-radiotracer...

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on healthy epithelial cells thus enabling the generation of breast tumor-specific radiolabeled immune therapeutic tools.Methods: MAb GGSK-1/30 was used for immunohistochemical analysis of human breast cancer tissue. Its desferrioxamine (Df')-conjugate was synthesized and labelled with 89Zr. [89Zr]Zr-Df'-GGSK-1/30 was evaluated as a potential PET tracer. Binding and pharmacokinetic properties of [89Zr]Zr-Df'-GGSK-1/30 were analyzed in vitro using human and murine cell lines that express tumor-associated MUC1. Self-generated primary murine breast cancer cells expressing human tumor-associated MUC1 were transplanted subcutaneously in wild type and human MUC1-transgenic mice. The pharmacology of [89Zr]Zr-Df'-GGSK-1/30 was investigated using breast tumor-bearing mice in vivo by PET/MRT imaging as well as by ex vivo organ biodistribution analysis.Results: The mAb GGSK-1/30 stained specifically human breast tumor tissue and can be possibly used to predict the severity of disease progression based on the expression of the tumor-associated MUC1. For in vivo imaging, the Df'-conjugated mAb was radiolabeled with a radiochemical yield of 60 %, a radiochemical purity of 95 % and an apparent specific activity of 6.1 GBq/µmol. After 7 d, stabilities of 84 % in human serum and of 93 % in saline were observed. In vitro cell studies showed strong binding to human tumor-associated MUC1 expressing breast cancer cells. The breast tumor-bearing mice showed an in vivo tumor uptake of >50 %ID/g and clearly visible specific enrichment of the radioconjugate via PET/MRT.Principal conclusions: Tumor-associated MUC1 is a very important biomarker for breast cancer next to the traditional markers estrogen receptor (ER), progesterone receptor (PR) and HER/2-neu. The mAb GGSK-1/30 can be used for the diagnosis of over 90% of breast cancers, including triple negative breast cancer based on biopsy staining. Its radioimmunoconjugate represents a promising PET-tracer for breast cancer imaging selectively targeting breast cancer cells.