3 research outputs found
Design, Synthesis, and Evaluation of a Low-Molecular-Weight <sup>11</sup>C‑Labeled Tetrazine for Pretargeted PET Imaging Applying Bioorthogonal in Vivo Click Chemistry
A low-molecular-weight
tetrazine labeled with the short-lived positron
emitter carbon-11 was developed as a bioorthogonal PET probe for pretargeted
imaging. A method for efficient and fast synthesis of this imaging
agent is presented using radiolabeling of a readily available precursor.
High reactivity with <i>trans</i>-cyclooctenes was observed
and in vivo investigations including PET/MR scanning showed homogeneous
biodistribution, good metabolic stability, and rapid excretion in
naive mice. These properties are key to the success of bioorthogonal <sup>11</sup>C-PET imaging, which has been shown in a simple pretargeting
experiment using TCO-modified mesoporous silica nanoparticles. Overall,
this <sup>11</sup>C-labeled tetrazine represents a highly versatile
and advantageous chemical tool for bioorthogonal PET imaging and enables
pretargeting approaches using carbon-11 for the first time
sj-pdf-1-jcb-10.1177_0271678X231202336 - Supplemental material for [<sup>11</sup>C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier
Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231202336 for [11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier by Severin Mairinger, Sarah Leterrier, Thomas Filip, Mathilde Löbsch, Jens Pahnke, Irene Hernández-Lozano, Johann Stanek, Nicolas Tournier, Markus Zeitlinger, Marcus Hacker, Oliver Langer and Thomas Wanek in Journal of Cerebral Blood Flow & Metabolism</p
Factors Governing P‑Glycoprotein-Mediated Drug–Drug Interactions at the Blood–Brain Barrier Measured with Positron Emission Tomography
The
adenosine triphosphate-binding cassette transporter P-glycoprotein
(ABCB1/Abcb1a) restricts at the blood–brain barrier (BBB) brain
distribution of many drugs. ABCB1 may be involved in drug–drug
interactions (DDIs) at the BBB, which may lead to changes in brain
distribution and central nervous system side effects of drugs. Positron
emission tomography (PET) with the ABCB1 substrates (<i>R</i>)-[<sup>11</sup>C]Âverapamil and [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide and the ABCB1 inhibitor tariquidar has allowed
direct comparison of ABCB1-mediated DDIs at the rodent and human BBB.
In this work we evaluated different factors which could influence
the magnitude of the interaction between tariquidar and (<i>R</i>)-[<sup>11</sup>C]Âverapamil or [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide at the BBB and thereby contribute to previously
observed species differences between rodents and humans. We performed <i>in vitro</i> transport experiments with [<sup>3</sup>H]Âverapamil
and [<sup>3</sup>H]-<i>N</i>-desmethyl-loperamide in ABCB1
and Abcb1a overexpressing cell lines. Moreover we conducted <i>in vivo</i> PET experiments and biodistribution studies with
(<i>R</i>)-[<sup>11</sup>C]Âverapamil and [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide in wild-type mice without and with
tariquidar pretreatment and in homozygous <i>Abcb1a/1b<sup>(−/−)</sup></i> and heterozygous <i>Abcb1a/1b<sup>(+/−)</sup></i> mice. We found no differences for <i>in vitro</i> transport of [<sup>3</sup>H]Âverapamil and [<sup>3</sup>H]-<i>N</i>-desmethyl-loperamide by ABCB1 and Abcb1a and its inhibition
by tariquidar. [<sup>3</sup>H]-<i>N</i>-Desmethyl-loperamide
was transported with a 5 to 9 times higher transport ratio than [<sup>3</sup>H]Âverapamil in ABCB1- and Abcb1a-transfected cells. <i>In vivo</i>, brain radioactivity concentrations were lower for
[<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide than for
(<i>R</i>)-[<sup>11</sup>C]Âverapamil. Both radiotracers
showed tariquidar dose dependent increases in brain distribution with
tariquidar half-maximum inhibitory concentrations (IC<sub>50</sub>) of 1052 nM (95% confidence interval CI: 930–1189) for (<i>R</i>)-[<sup>11</sup>C]Âverapamil and 1329 nM (95% CI: 980–1801)
for [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide. In homozygous <i>Abcb1a/1b<sup>(−/−)</sup></i> mice brain radioactivity
distribution was increased by 3.9- and 2.8-fold and in heterozygous <i>Abcb1a/1b<sup>(+/−)</sup></i> mice by 1.5- and 1.1-fold,
for (<i>R</i>)-[<sup>11</sup>C]Âverapamil and [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide, respectively, as compared
with wild-type mice. For both radiotracers radiolabeled metabolites
were detected in plasma and brain. When brain and plasma radioactivity
concentrations were corrected for radiolabeled metabolites, brain
distribution of (<i>R</i>)-[<sup>11</sup>C]Âverapamil and
[<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide was increased
in tariquidar (15 mg/kg) treated animals by 14.1- and 18.3-fold, respectively,
as compared with vehicle group. Isoflurane anesthesia altered [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide but not (<i>R</i>)-[<sup>11</sup>C]Âverapamil metabolism, and this had a
direct effect on the magnitude of the increase in brain distribution
following ABCB1 inhibition. Our data furthermore suggest that in the
absence of ABCB1 function brain distribution of [<sup>11</sup>C]-<i>N</i>-desmethyl-loperamide but not (<i>R</i>)-[<sup>11</sup>C]Âverapamil may depend on cerebral blood flow. In conclusion,
we have identified a number of important factors, i.e., substrate
affinity to ABCB1, brain uptake of radiolabeled metabolites, anesthesia,
and cerebral blood flow, which can directly influence the magnitude
of ABCB1-mediated DDIs at the BBB and should therefore be taken into
consideration when interpreting PET results