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A Bronsted Acidic Gallium Hydride: Facile Interconversion of NNNN-Macrocycle Supported [Ga^I ]⁺ and [Ga^III H]².

ABSTRACT: Protonolysis of [Cp*M] (M=Ga, In, Tl) with [(Me₄ TACD)H][BAr₄ ^Me ] (Me₄ TACD=N,N',N'',N'''-tetramethyl-1,4,7,10-tetraazacyclododecane; [BAr₄ ^Me ]^- =[B{C₆ H₃ -3,5-(CH₃ )₂ }₄ ]^- ) provided monovalent salts [(Me₄ TACD)M][BAr₄ ^Me ], whereas [Cp*Al]₄ yielded trivalent [(Me₄ TACD)AlH][BAr₄ ^Me ]₂ . Protonation of [(Me₄ TACD)Ga][BAr₄ ^Me ] with [Et₃ NH][BAr₄ ^Me ] gave an unusually acidic (pK_a (CH₃ CN)=24.5) gallium(III) hydride dication [(Me₄ TACD)GaH][BAr₄ ^Me ]₂ . Deprotonation with IMe₄ (1,3,4,5-tetramethyl-imidazol-ylidene) returned [(Me₄ TACD)Ga][BAr₄ ^Me ]. These reversible processes occur with formal two-electron oxidation and reduction of gallium. DFT calculations suggest that gallium(I) protonation is facilitated by strong coordination of the tetradentate ligand, which raises the HOMO energy. High nuclear charge of [(Me₄ TACD)GaH]²⁺ facilitates hydride-to-metal charge transfer during deprotonation. Attempts to prepare a gallium(III) dihydride cation resulted in spontaneous dehydrogenation to [(Me₄ TACD)Ga]⁺ .

SUBMITTER: Morris LJ

PROVIDER: S-EPMC9304309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction[68Ga]Ga-P15-041 ([68Ga]Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer that can be generator-produced. We undertook a Phase 0/I clinical trial to assess its potential for imaging bone metastases in prostate cancer including assessment of radiotracer biodistribution and dosimetry.MethodsSubjects with prostate cancer and known or suspected osseous metastatic disease were enrolled into one of two arms: dosimetry or dynamic. Dosimetry was performed with 6 whole body PET acquisitions and urine collection spanning 3 h; normal organ dosimetry was calculated using OLINDA/EXM. Dynamic imaging included a 60 min acquisition over a site of known or suspected disease followed by two whole body scans. Bootstrapping and subsampling of the acquired list-mode data were conducted to recommend image acquisition parameters for future clinical trials.ResultsUp to 233 MBq (6.3 mCi) of [68Ga]Ga-P15-041 was injected into 12 enrolled volunteers, 8 in dosimetry and 4 in dynamic cohorts. Radiotracer accumulated in known bone lesions and cleared rapidly from blood and soft tissue. The highest individual organ dose was 0.135 mSv/MBq in the urinary bladder wall. The average effective dose was 0.0173 ± 0.0036 mSv/MBq. An average injected activity of 166.5 MBq (4.5 mCi) resulted in absorbed dose estimates of 22.5 mSv to the urinary bladder wall, 8.2 mSv to the kidneys, and an effective dose of 2.9 mSv. Lesion signal to noise ratios on images generated from subsampled data were significantly higher for injected activities above 74 MBq (2 mCi) and were also significantly higher for imaging at 90 min than at 180 min post-injection.ConclusionsDosimetry estimates are acceptable and [68Ga]Ga-P15-041 uptake characteristics in patients with confirmed bone metastases support its continued development.Advances in knowledge and implications for patient careUse of [68Ga]Ga-P15-041 would not require cyclotron infrastructure for manufacturing and distribution, allowing for improved patient access to a promising PET bone imaging agent.

Project description:PurposeThe widespread use of 68Ga 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 68Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr3]octreotide (TOC), a somatostatin subtype 2 receptor (SST2)-targeting vector for imaging and functional characterisation of SSTR2 expressing tumours.MethodsThe radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex natGa(III) and 68Ga(III). Competition binding assays of [natGa]Ga-DATA-TOC or [natGa]Ga-DOTA-TOC against [125I-Tyr25]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST2,3,5 receptor subtypes (HEK293-hSST2/3/5 cells). First in vivo studies were performed in female NMRI-nude mice bearing SST2-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST2-specific tumour-targeting of [68Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [68Ga]Ga-DOTA-TOC reference. A direct comparison of [68Ga]Ga-DATA-TOC with the well-established PET radiotracer [68Ga]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 [68Ga]Ga-DATA-TOC.ResultsDATA-TOC was labelled with 68Ga 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 hSST2-affinities of [natGa]Ga-DATA-TOC and [natGa]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC50 values. In mice, [68Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [68Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two 68Ga-radiotracers, but with a higher tumour-to-liver contrast for [68Ga]Ga-DATA-TOC.Conclusion[68Ga]Ga-DATA-TOC was prepared, to a quality appropriate for in vivo use, following a highly efficient kit type process. Furthermore, the novel radiopharmaceutical was comparable or better than [68Ga]Ga-DOTA-TOC in all preclinical tests, achieving a higher tumour-to-liver contrast in a NET-patient. The results illustrate the potential of the DATA-chelator to facilitate the access to and preparation of 68Ga-radiotracers in a routine clinical radiopharmacy setting.

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A Bronsted Acidic Gallium Hydride: Facile Interconversion of NNNN-Macrocycle Supported [GaI ]+ and [GaIII H]2.

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A Bronsted Acidic Gallium Hydride: Facile Interconversion of NNNN-Macrocycle Supported [Ga^I ]⁺ and [Ga^III H]².