Automated radiosynthesis of [<sup>18</sup>F]SPA‐RQ for imaging human brain NK<sub>1</sub> receptors with PET

Chin, Frederick T.; Morse, Cheryl L.; Shetty, Hitesh; Pike, Victor W.

doi:10.1002/jlcr.1016

Cited by 30 publications

(27 citation statements)

References 17 publications

(23 reference statements)

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“…In addition to binding IC 50 , lipophilicity and suitability for 18 F- or 11 C-labeling, selection of BMS-732098 and BMS-721313 was based on their CRF 1 receptor specificity using in vitro autoradiography and biodistribution studies in rat. BMS-732098 and BMS-721313 were labeled by treating the corresponding desfluoromethyl precursors with [ 18 F]bromofluoromethane, itself generated from cyclotron-produced [ 18 F]fluoride ion [22]. Ligand BMS-709460 was labeled by treating the phenolic analog with [ 11 C]iodomethane.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Lodge

Chin

et al. 2014

Nuclear Medicine and Biology

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Introduction A radioligand for measuring the density of corticotrophin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)pyrazin-2(1H)-one scaffold. Methods CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF receptors (displacement of [125I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF receptor ligand, [3H]BMS-728300. Results The three ligands selected for development showed high binding affinity (IC50 values, 0.3–8 nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8–4.4). [3H]BMS-728300 and the two 18F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50–120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [18F]BMS-721313, [18F]BMS-732098 and [11C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.

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Section: Resultsmentioning

confidence: 99%

“…Potassium carbonate (0.5 mg) and K 2.2.2 (5.0 mg) in H 2 O-MeCN (1: 9 v/v; 100 αL) were added to the radioactive solution and delivered to a TRACERlab Fx FN module (GE Medical Systems) equipped with a secondary Peltier-cooling and heating device [22]. This solution was dried by two cycles of addition and evaporation of acetonitrile (2 mL).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Lodge

Chin

et al. 2014

Nuclear Medicine and Biology

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“…[ 18 F]SPA-RQ, produced as previously described (6), was obtained in high radiochemical purity (>99%) and specific activity at time of injection was 53 ± 20 GBq/μmol. After a transmission scan, [ 18 F]SPA-RQ (319 ± 58 MBq) was injected intravenously over ∼1 min, and subjects were scanned on a GE Advance camera (GE Healthcare, Waukesha, Wisconsin).…”

Section: Methodsmentioning

confidence: 99%

Decreased Neurokinin-1 (Substance P) Receptor Binding in Patients with Panic Disorder: Positron Emission Tomographic Study with [18F]SPA-RQ

Fujimura

Yasuno

Farris

et al. 2009

Biological Psychiatry

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Background Positron emission tomography (PET) can localize and quantify neurokinin-1 (NK1) receptors in brain using the nonpeptide antagonist radioligand, [18F]SPA-RQ. We sought to determine if patients with panic disorder have altered density of NK1 receptors in brain because of their history of recurrent panic attacks. We also sought to determine if a drug-induced panic attack releases substance P in brain, as measured by decreased binding of [18F]SPA-RQ. Methods Positron emission tomography scans with [18F]SPA-RQ were performed in 14 patients with panic disorder and 14 healthy subjects. Of these two groups, 7 patients and 10 healthy subjects were scanned twice, once at baseline and once after injection of doxapram, a drug that induces panic attacks. Results NK1 receptor binding in patients (n = 14) compared with that in healthy subjects (n = 14) was significantly decreased by 12% to 21% in all brain regions. Doxapram effectively produced panic attacks in 6 of 7 patients with panic disorder but only 2 of 10 healthy subjects. Doxapram caused no significant change of [18F]SPA-RQ binding in either patients or healthy subjects. Conclusions Although induction of a panic attack has no significant effect on [18F]SPA-RQ binding to NK1 receptors, patients with panic disorder have widespread reduction of NK1 receptor binding in brain.

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“…Although previously several electrophilic monofluoromethylations of oxygen-, sulphur-, nitrogen-, and carbon nucleophiles have been reported with CH 2 FI [49][50][51], CH 2 FBr [52][53][54][55][56][57][58], CH 2 FCl [56,[59][60][61], or CH 2 FOSO 2 R (R = CF 3 , CH 3 , tolyl) [55,62] as monofluoromethylating agents, their use was restricted to 18 F-labelling.…”

Section: A-fluoromethyl Ethersmentioning

confidence: 99%

New trends in the chemistry of α-fluorinated ethers, thioethers, amines and phosphines

Manteau

Pazenok

Vors

et al. 2010

Journal of Fluorine Chemistry

357

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Automated radiosynthesis of [¹⁸F]SPA‐RQ for imaging human brain NK₁ receptors with PET

Cited by 30 publications

References 17 publications

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Decreased Neurokinin-1 (Substance P) Receptor Binding in Patients with Panic Disorder: Positron Emission Tomographic Study with [18F]SPA-RQ

New trends in the chemistry of α-fluorinated ethers, thioethers, amines and phosphines

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Automated radiosynthesis of [18F]SPA‐RQ for imaging human brain NK1 receptors with PET

Cited by 30 publications

References 17 publications

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Decreased Neurokinin-1 (Substance P) Receptor Binding in Patients with Panic Disorder: Positron Emission Tomographic Study with [18F]SPA-RQ

New trends in the chemistry of α-fluorinated ethers, thioethers, amines and phosphines

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Automated radiosynthesis of [¹⁸F]SPA‐RQ for imaging human brain NK₁ receptors with PET