Positron Emission Tomography–Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A

Zhou, Iris Yuwen; Ramsay, Ian; Ay, İlknur; Pantazopoulos, Pamela; Rotile, Nicholas J.; Wong, Alison; Caravan, Peter; Gale, Eric M.

doi:10.1097/rli.0000000000000736

Cited by 27 publications

(36 citation statements)

References 39 publications

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“…Rapid excretion and complete clearance of MRI contrast agents after diagnostic imaging are essential for their safe clinical use, especially considering the potential toxic side effects related to prolonged Gd tissue retention. 44 , 45 The preclinical assessment has shown that MT218 possesses pharmacokinetics, excretion, and tissue retention similar to gadoteridol, one of the safest macrocyclic GBCAs, and other clinical macrocyclic GBCAs. 46 Greater than 80% of the injected dose is excreted in urine within the first 8 hours postinjection in rats after a single dose.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Gao

Jiang

et al. 2022

Invest Radiol

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Objectives Preclinical assessments were performed according to the US Food and Drug Administration guidelines to determine the physicochemical properties, pharmacokinetics, clearance, safety, and tumor-specific magnetic resonance (MR) imaging of MT218, a peptidic gadolinium-based MR imaging agent targeting to extradomain B fibronectin for MR molecular imaging of aggressive tumors. Materials and Methods Relaxivity, chelation stability, binding affinity, safety-related target profiling, and effects on CYP450 enzymes and transporters were evaluated in vitro. Magnetic resonance imaging was performed with rats bearing prostate cancer xenografts, immunocompetent mice bearing murine pancreatic cancer allografts, and mice bearing lung cancer xenografts at different doses of MT218. Pharmacological effects on cardiovascular, respiratory, and central nervous systems were determined in rats and conscious beagle dogs. Pharmacokinetics were tested in rats and dogs. Biodistribution and excretion were studied in rats. Single and repeated dosing toxicity was evaluated in rats and dogs. In vitro and in vivo genotoxicity, in vitro hemolysis, and anaphylactic reactivity were also performed. Results At 1.4 T, the r 1 and r 2 relaxivities of MT218 were 5.43 and 7.40 mM −1 s −1 in pure water, 6.58 and 8.87 mM −1 s −1 in phosphate-buffered saline, and 6.54 and 8.70 mM −1 s −1 in aqueous solution of human serum albumin, respectively. The binding affinity of MT218 to extradomain B fragment is 3.45 μM. MT218 exhibited no dissociation of the Gd(III) chelates under physiological conditions. The peptide degradation half-life ( t 1/2 ) of MT218 was 1.63, 5.85, and 2.63 hours in rat, dog, and human plasma, respectively. It had little effect on CYP450 enzymes and transporters. MT218 produced up to 7-fold increase of contrast-to-noise ratios in the extradomain B fibronectin–rich tumors with a dose of 0.04 mmol/kg for at least 30 minutes. MT218 had little pharmacological effect on central nervous, cardiovascular, or respiratory systems. MT218 had a mean plasma elimination half-life ( t 1/2 ) of 0.31 and 0.89 hours in rats and dogs at 0.1 mmol/kg, respectively. No detectable Gd deposition was observed in the brain at 6 hours postinjection of MT218 at 0.1 mmol/kg in rats. MT218 was not mutagenic and had no mortality or morbidity in the rats or dogs up to 1.39 and 0.70 mmol/kg/d, respectively. The no observed adverse effect level of MT218 in Sprague-Dawley rats was 1.39 mmol/kg for single dosing and 0.46 mmol/kg/d for repeated dosing. The no observed adverse effect level in dogs was 0.07 mmol/kg/d. MT218 exhibited no genotoxicity, hemolysis, and anaphylacti...

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Section: Discussionmentioning

confidence: 99%

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Gao

Jiang

et al. 2022

Invest Radiol

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“…Thus, for in vivo applications, it is critical to achieve as high a stability as possible to minimize the risk of Mn(II) dissociation in the body. This is also true for emerging applications involving Mn-52 PET imaging. , Concurrently, Mn-based MRI contrast agents require the presence of an inner-sphere water ligand to increase the relaxivity of the complex, and leaving a coordination site vacant for water access may result in lower stability. Finally, the large size of the Mn(II) ion and lack of LFSE results in coordination numbers of 6, 7, and 8 for complexes in aqueous solution, and coordination number is difficult to predict a priori.…”

Section: Discussionmentioning

confidence: 99%

Thermodynamic Stability of Mn(II) Complexes with Aminocarboxylate Ligands Analyzed Using Structural Descriptors

et al. 2022

Self Cite

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We present a quantitative analysis of the thermodynamic stabilities of Mn(II) complexes, defined by the equilibrium constants (log K MnL values) and the values of pMn obtained as −log[Mn] free for total metal and ligand concentrations of 1 and 10 μM, respectively. We used structural descriptors to analyze the contributions to complex stability of different structural motifs in a quantitative way. The experimental log K MnL and pMn values can be predicted to a good accuracy by adding the contributions of the different motifs present in the ligand structure. This allowed for the identification of features that provide larger contributions to complex stability, which will be very helpful for the design of efficient chelators for Mn(II) complexation. This issue is particularly important to develop Mn(II) complexes for medical applications, for instance, as magnetic resonance imaging (MRI) contrast agents. The analysis performed here also indicates that coordination number eight is more common for Mn(II) than is generally assumed, with the highest log K MnL values generally observed for hepta- and octadentate ligands. The X-ray crystal structure of [Mn 2 (DOTA)(H 2 O) 2 ], in which eight-coordinate [Mn(DOTA)] 2– units are bridged by six-coordinate exocyclic Mn(II) ions, is also reported.

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“…Zhou et al recently used 52 Mn-labelled chelators to investigate the biodistribution and elimination of nat Mn-based MRI agents. [45] Additionally, Vanasschen et al proposed the radiolabelling of CDTA with isotopic mixtures of 52 Mn/ nat Mn to produce a bimodal imaging probe made up of two chemically identical contrast agents. [46] These approaches could be applied to Mn(III) porphyrin MRI agents to allow the assessment of the concentration of the probe based on image and ex vivo biodistribution.…”

Section: Discussionmentioning

confidence: 99%

Microwave-assisted radiolabelling of 52Mn-porphyrins: applications in cell and liposome radiolabelling

Gawne

Pinto

Nielsen

et al. 2022

Preprint

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Manganese porphyrins have several therapeutic/imaging applications, including their use as radioprotectants (in clinical trials) and as paramagnetic MRI contrast agents. The affinity of porphyrins for lipid bilayers also makes them candidates for cell/liposome labelling. We hypothesised that metalation with the positron emission tomography (PET) radionuclide 52Mn (t1/2 = 5.6 d) would allow long-term in vivo biodistribution studies of Mn-porphyrins as well as a method to label and track cells/liposomes, but methods for fast and efficient radiolabelling are lacking. Several porphyrins were produced and radiolabelled by addition to neutralised [52Mn]MnCl2 and heated using a microwave (MW) synthesiser and compared with non-MW heating. MW radiosynthesis allowed >95 % radiochemical yields (RCY) in just 1 h. Conversely, non-MW heating at 70 oC for 1 h resulted in low RCY (0 – 25 % RCY) and most porphyrins did not reach radiolabelling completion after 24 h. Formation of the 52Mn-complexes were confirmed with radio-HPLC by comparison with their non-radioactive 55Mn counterparts. Following this, several 52Mn-porphyrins were used to radiolabel liposomes resulting in 75 – 86 % labelling efficiency (LE). Two lead 52Mn-porphyrins were taken forward to label MDA-MB-231 cancer cells in vitro, achieving ca. 11 % LE. After 24 h, 32 – 45 % of the 52Mn-porphyrin was retained in cells. In contrast to standard methods, MW heating allows the fast synthesis of 52Mn-porphyrins with >95% radiochemical yields that avoid purification. 52Mn-porphyrins also show promising cell/liposome labelling properties. Our reported technique can potentially be exploited for the in vivo imaging of Mn-porphyrin therapeutics, as well as for the accurate in vivo quantification of Mn-porphyrin MRI agents.

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Positron Emission Tomography–Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A

Cited by 27 publications

References 39 publications

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Thermodynamic Stability of Mn(II) Complexes with Aminocarboxylate Ligands Analyzed Using Structural Descriptors

Microwave-assisted radiolabelling of 52Mn-porphyrins: applications in cell and liposome radiolabelling

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