A low-molecular-weight (18) F-labeled tetrazine derivative was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of (18) F through additional steps were evaded by direct (18) F-fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddition with trans-cyclooctenes were investigated by applying quantum chemical calculations and stopped-flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile-tagged (bio)molecules. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the (18) F-labeled tetrazine that also passes the blood-brain barrier. An in vivo click experiment confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chemical and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research.
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 trans-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 (11)C-PET imaging, which has been shown in a simple pretargeting experiment using TCO-modified mesoporous silica nanoparticles. Overall, this (11)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.
In the present study, the influence of stress from handling and transport on some frequently examined blood parameters of racing pigeons was evaluated. After 3 hr, there was a highly significant (P < 0.01) increase in the number as well as in the percentage of heterophils and decrease of lymphocytes. In clinical chemistries, increases of creatine kinase and glucose and a decrease of uric acid were observed. There was a mean decrease of the total white blood count of >15% that was less significant (P < 0.05). Changes in lactate dehydrogenase, basophils, and monocytes did not prove to be significant; eosinophils, aspartate aminotransferase, total protein, and the packed cell volume were not influenced by stress.
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 (R)-[11C]verapamil and [11C]-N-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 (R)-[11C]verapamil or [11C]-N-desmethyl-loperamide at the BBB and thereby contribute to previously
observed species differences between rodents and humans. We performed in vitro transport experiments with [3H]verapamil
and [3H]-N-desmethyl-loperamide in ABCB1
and Abcb1a overexpressing cell lines. Moreover we conducted in vivo PET experiments and biodistribution studies with
(R)-[11C]verapamil and [11C]-N-desmethyl-loperamide in wild-type mice without and with
tariquidar pretreatment and in homozygous Abcb1a/1b(−/−) and heterozygous Abcb1a/1b(+/−) mice. We found no differences for in vitro transport of [3H]verapamil and [3H]-N-desmethyl-loperamide by ABCB1 and Abcb1a and its inhibition
by tariquidar. [3H]-N-Desmethyl-loperamide
was transported with a 5 to 9 times higher transport ratio than [3H]verapamil in ABCB1- and Abcb1a-transfected cells. In vivo, brain radioactivity concentrations were lower for
[11C]-N-desmethyl-loperamide than for
(R)-[11C]verapamil. Both radiotracers
showed tariquidar dose dependent increases in brain distribution with
tariquidar half-maximum inhibitory concentrations (IC50) of 1052 nM (95% confidence interval CI: 930–1189) for (R)-[11C]verapamil and 1329 nM (95% CI: 980–1801)
for [11C]-N-desmethyl-loperamide. In homozygous Abcb1a/1b(−/−) mice brain radioactivity
distribution was increased by 3.9- and 2.8-fold and in heterozygous Abcb1a/1b(+/−) mice by 1.5- and 1.1-fold,
for (R)-[11C]verapamil and [11C]-N-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 (R)-[11C]verapamil and
[11C]-N-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 [11C]-N-desmethyl-loperamide but not (R)-[11C]verapamil 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 [11C]-N-desmethyl-loperamide but not (R)-[11C]verapamil may depend on cerebral blood flow. In conclusion,
we have identified a number of important factors, i.e., substrate
affinity to ABCB1...
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