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A bisphosphonate for (19)F-magnetic resonance imaging.

Kenny GD, Shaw KP, Sivachelvam S, White AJ, Botnar RM, T M de Rosales R - J Fluor Chem (2016)

Bottom Line: The potential of (19)F-BP to provide contrast was analysed in vitro and in vivo using (19)F-MRI.The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of (19)F-BP, showing uptake in the liver and in the bladder/urinary system areas.However, bone uptake was not observed.

View Article: PubMed Central - PubMed

Affiliation: Division of Imaging Sciences & Biomedical Engineering, King's College London, St Thomas' Hospital, London SE1 7EH, UK.

ABSTRACT

(19)F-magnetic resonance imaging (MRI) is a promising technique that may allow us to measure the concentration of exogenous fluorinated imaging probes quantitatively in vivo. Here, we describe the synthesis and characterisation of a novel geminal bisphosphonate ((19)F-BP) that contains chemically-equivalent fluorine atoms that show a single and narrow (19)F resonance and a bisphosphonate group that may be used for labelling inorganic materials based in calcium phosphates and metal oxides. The potential of (19)F-BP to provide contrast was analysed in vitro and in vivo using (19)F-MRI. In vitro studies demonstrated the potential of (19)F-BP as an MRI contrast agent in the millimolar concentration range with signal-to-noise ratios (SNR) comparable to previously reported fluorinated probes. The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of (19)F-BP, showing uptake in the liver and in the bladder/urinary system areas. However, bone uptake was not observed. In addition, (19)F-BP showed undesirable toxicity effects in mice that prevent further studies with this compound at the required concentrations for MRI contrast. This study highlights the importance of developing (19)F MRI probes with the highest signal intensity achievable.

No MeSH data available.


Related in: MedlinePlus

Animal MR imaging study (see Section 4 for details). A mouse was injected with 19F-BP i.v. (108 mM in PBS buffer) and imaged using 1H (left column) and 19F MRI (middle column), which were overlayed to determine location (right column). Top row is an axial slice through the bladder/urinary tract area, second row an axial slice through the knees (arrows) and the third row an axial slice through the liver. A vial containing a known amount of 19F-BP was positioned next to the animal for reference.
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fig0015: Animal MR imaging study (see Section 4 for details). A mouse was injected with 19F-BP i.v. (108 mM in PBS buffer) and imaged using 1H (left column) and 19F MRI (middle column), which were overlayed to determine location (right column). Top row is an axial slice through the bladder/urinary tract area, second row an axial slice through the knees (arrows) and the third row an axial slice through the liver. A vial containing a known amount of 19F-BP was positioned next to the animal for reference.

Mentions: Preliminary in vivo studies were carried out in a 9.4 T scanner with a healthy mouse. We have recently shown that bifunctional BPs accumulate in areas of high bone metabolism such as the end of long bones and bone metastases using SPECT imaging [17], [18]. Hence, we expected 19F-BP to accumulate in bone. However, after intravenous injection, only signals in the bladder/urinary system and liver areas were detected, the former most probably due to renal excretion as expected for a molecule of this size (Fig. 3A) although this cannot be confirmed with the data available. In addition, uptake in other tissues/organs of the same area such as the uterus cannot be ruled out. It is important to note that the 19F and 1H acquisitions were not performed simultaneously and each modality was acquired with different slice thicknesses (19F is 5 times thicker than the 1H image), complicating the interpretation of the images. Motion artifacts could also be responsible for the suboptimal overlay of the two modalities. The signal observed in the liver area (Fig. 3C), which is a much bigger organ and hence less affected by these issues (Fig. 3C), is more conclusive to uptake by this organ. Liver uptake is common for lipophilic molecules, and since fluorination is known to increase the lipophilicity of compounds, it is likely to be the result of the trifluoromethyl group. We believe that the lack of bone uptake may be the result of its high lipophilicity, compared to non-fluorinated BPs, resulting in higher liver uptake, and/or fast renal clearance. Indeed, recent reports support the notion that fluorinated groups increase the renal excretion of molecules in vivo[22]. Another interesting possibility is that bone binding could have resulted in a chemical shift of the 19F resonance that could result in a lack of signal from bone. However, the presence of the expected single resonance in the broad sweep width spectrum performed prior to the imaging session strongly suggests this is not the case.


A bisphosphonate for (19)F-magnetic resonance imaging.

Kenny GD, Shaw KP, Sivachelvam S, White AJ, Botnar RM, T M de Rosales R - J Fluor Chem (2016)

Animal MR imaging study (see Section 4 for details). A mouse was injected with 19F-BP i.v. (108 mM in PBS buffer) and imaged using 1H (left column) and 19F MRI (middle column), which were overlayed to determine location (right column). Top row is an axial slice through the bladder/urinary tract area, second row an axial slice through the knees (arrows) and the third row an axial slice through the liver. A vial containing a known amount of 19F-BP was positioned next to the animal for reference.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834630&req=5

fig0015: Animal MR imaging study (see Section 4 for details). A mouse was injected with 19F-BP i.v. (108 mM in PBS buffer) and imaged using 1H (left column) and 19F MRI (middle column), which were overlayed to determine location (right column). Top row is an axial slice through the bladder/urinary tract area, second row an axial slice through the knees (arrows) and the third row an axial slice through the liver. A vial containing a known amount of 19F-BP was positioned next to the animal for reference.
Mentions: Preliminary in vivo studies were carried out in a 9.4 T scanner with a healthy mouse. We have recently shown that bifunctional BPs accumulate in areas of high bone metabolism such as the end of long bones and bone metastases using SPECT imaging [17], [18]. Hence, we expected 19F-BP to accumulate in bone. However, after intravenous injection, only signals in the bladder/urinary system and liver areas were detected, the former most probably due to renal excretion as expected for a molecule of this size (Fig. 3A) although this cannot be confirmed with the data available. In addition, uptake in other tissues/organs of the same area such as the uterus cannot be ruled out. It is important to note that the 19F and 1H acquisitions were not performed simultaneously and each modality was acquired with different slice thicknesses (19F is 5 times thicker than the 1H image), complicating the interpretation of the images. Motion artifacts could also be responsible for the suboptimal overlay of the two modalities. The signal observed in the liver area (Fig. 3C), which is a much bigger organ and hence less affected by these issues (Fig. 3C), is more conclusive to uptake by this organ. Liver uptake is common for lipophilic molecules, and since fluorination is known to increase the lipophilicity of compounds, it is likely to be the result of the trifluoromethyl group. We believe that the lack of bone uptake may be the result of its high lipophilicity, compared to non-fluorinated BPs, resulting in higher liver uptake, and/or fast renal clearance. Indeed, recent reports support the notion that fluorinated groups increase the renal excretion of molecules in vivo[22]. Another interesting possibility is that bone binding could have resulted in a chemical shift of the 19F resonance that could result in a lack of signal from bone. However, the presence of the expected single resonance in the broad sweep width spectrum performed prior to the imaging session strongly suggests this is not the case.

Bottom Line: The potential of (19)F-BP to provide contrast was analysed in vitro and in vivo using (19)F-MRI.The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of (19)F-BP, showing uptake in the liver and in the bladder/urinary system areas.However, bone uptake was not observed.

View Article: PubMed Central - PubMed

Affiliation: Division of Imaging Sciences & Biomedical Engineering, King's College London, St Thomas' Hospital, London SE1 7EH, UK.

ABSTRACT

(19)F-magnetic resonance imaging (MRI) is a promising technique that may allow us to measure the concentration of exogenous fluorinated imaging probes quantitatively in vivo. Here, we describe the synthesis and characterisation of a novel geminal bisphosphonate ((19)F-BP) that contains chemically-equivalent fluorine atoms that show a single and narrow (19)F resonance and a bisphosphonate group that may be used for labelling inorganic materials based in calcium phosphates and metal oxides. The potential of (19)F-BP to provide contrast was analysed in vitro and in vivo using (19)F-MRI. In vitro studies demonstrated the potential of (19)F-BP as an MRI contrast agent in the millimolar concentration range with signal-to-noise ratios (SNR) comparable to previously reported fluorinated probes. The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of (19)F-BP, showing uptake in the liver and in the bladder/urinary system areas. However, bone uptake was not observed. In addition, (19)F-BP showed undesirable toxicity effects in mice that prevent further studies with this compound at the required concentrations for MRI contrast. This study highlights the importance of developing (19)F MRI probes with the highest signal intensity achievable.

No MeSH data available.


Related in: MedlinePlus