A novel 7-((4-(3-((2-[
18
F]fluoropyridin-3-yl)oxy)propyl)-1
H
-1,2,3-triazol-1-yl)methyl)-1
H
-benzo[
d
]imidazole derivative of the angiotensin
II type-1 receptor
(AT
1
R) blocker candesartan, [
18
F]fluoropyridine–candesartan,
was synthesized via the copper-catalyzed azide–alkyne cycloaddition
click reaction between 2-[
18
F]fluoro-3-(pent-4-yn-1-yloxy)pyridine
([
18
F]FPyKYNE) and the tetrazole-protected azido-candesartan
derivative, followed by acid deprotection. This three-step, two-pot,
and two-step purification synthesis was done within 2 h. The use of
tris[(1-hydroxypropyl-1
H
-1,2,3-triazol-4-yl)methyl]amine
(THPTA) as a Cu(I) stabilizing agent increased the overall radiochemical
yield by 4-fold (10 ± 2%,
n
= 13) compared to
the reaction without THPTA (2.4 ± 0.2%,
n
=
3; decay-corrected from
18
F produced at the end-of-beam).
Complete separation of [
18
F]FPyKYNE from its nitro precursor
and [
18
F]fluoropyridine–candesartan from the deprotected
azido-candesartan allowed for high molar activities (>380 GBq/μmol)
of the tracer. The use of 0.1% trifluoroacetic acid in water for reformulation
and the addition of sodium ascorbate to the final formulation (1.6
± 0.2 GBq/mL,
n
= 3) prevented tracer radiolysis
with >97% radiochemical purity for a period of up to 10 h after
the
end-of-synthesis. A significant reduction in the uptake (86 ±
3%,
n
= 8) of the tracer was observed ex vivo in
rats (at 20 min postinjection) in the AT
1
R-rich kidney
cortex following pretreatment with saturating doses of the AT
1
R antagonist candesartan or losartan. This specific binding
to AT
1
R was confirmed in vitro in the rat renal cortex
(autoradiography) by a reduction of 26 ± 5% (
n
= 12) with losartan coincubation (10 μM). These favorable
binding properties support further studies to assess the potential
of [
18
F]fluoropyridine–candesartan as a tracer for
the positron emission tomography imaging of renal AT
1
R.
blocker losartan is used in patients with renal and cardiovascular diseases. [ 18 F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT 1 R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [ 18 F]fluoropyridine-losartan in very high molar activity. Automated radiosynthesis was performed in a three-step, two-pot, and two-HPLCpurification procedure within 2 h. Pure [ 18 F]FPyKYNE was obtained by radiofluorination of NO 2 PyKYNE and silica-gel-HPLC purification (40 ± 9%), preventing the formation of nitropyridine-losartan in the second step. Conjugation with trityl-losartan azide via click chemistry, followed by acid hydrolysis, C18-HPLC purification and reformulation provided [ 18 F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [ 18 F]fluoride, EOB). Using tris [(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]-amine (THPTA) as a Cu(I)stabilizing agent for coupling [ 18 F]FPyKYNE to the unprotected losartan azide afforded [ 18 F]fluoropyridine-losartan in similar yields (11 ± 3%, decaycorrected from [ 18 F]fluoride, EOB). Reverse-phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high
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