Imaging of cAMP-specific phosphodiesterase-IV: Comparison of [11C]Rolipram and [11C]Ro 20-1724 in rats

Abstract

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20-1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20-1724. [nC]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [n1C]rolipram and [11C]Ro 20-1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20-1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20-1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20-1724, is a promising radioligand for imaging the PDEIV enzymes with PET.

Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction

“…Subjecting this intermediate to the adapted SAW conditions next afforded RO 20–1724 in 63% yield. This new route does not only decrease the step count significantly (previously reported: 7 steps), but, according to the report by the Audisio lab, also bears the potential to introduce short-lived isotopes through the use of labeled CO 2 in the last step …”

Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction

“…Subjecting this intermediate to the adapted SAW conditions next afforded RO 20–1724 in 63% yield. This new route does not only decrease the step count significantly (previously reported: 7 steps), but, according to the report by the Audisio lab, also bears the potential to introduce short-lived isotopes through the use of labeled CO 2 in the last step …”

Rolipram Attenuates MK-801-Induced Deficits in Latent Inhibition.

“…Although brain levels of cAMP and rolipram binding were not measured in the present research, the attenuating effect of rolipram on NMDA-induced deficits in latent inhibition of cued fear conditioning is presumably due to an amplification of the cAMP-PKA signaling pathway through PDE4 inhibition in brain regions that support learning of the task. Studies devoted to examining rolipram binding in the brain (Kaulen, Bruning, Schneider, Sarter, & Baumgarten, 1989; Krause & Kuhne, 1988; Lourenco, DaSilva, Warsh, Wilson, & Houle, 1999; Lourenco et al, 2001; Randt et al, 1982; Schneider, Schmiechen, Brezinski, & Seidler, 1986) suggest that rolipram binds in a number of brain regions that may support latent inhibition learning, including the hippocampus (Han, Gallagher, & Holland, 1995; Kaye & Pearce, 1987; Oswald et al, 2002; Pouzet, Zhang, Weiner, Feldon, & Yee, 2004; Schmajuk, Christiansen, & Cox, 2000; Schmajuk, Lam, & Christiansen, 1994) and the amygdala (Coutureau, Blundell, & Killcross, 2001; Schauz & Koch, 2000). Lourenco et al (2001) demonstrated through competition studies that doses of rolipram as low as 0.05 mg/kg significantly reduce binding of radioactively labeled rolipram in a number of regions of the brain, including the hippocampus.…”

Whole-body biodistribution and radiation dosimetry in monkeys and humans of the phosphodiesterase 4 radioligand [11C](R)-rolipram: comparison of two-dimensional planar, bisected and quadrisected image analyses

“…Mean residence times were calculated based on the imaging data acquired from three different monkeys by using the weighting factor described in Materials and Methods to convert to human values ( Table 1). Based on these residence times, the organs with the highest radiation doses (µGy/MBq) were the urinary bladder wall (57), kidneys (26), liver (12), and lungs (11). The estimated human effective dose from the monkey 2D planar analysis was 6.6 µGy/MBq, which was 40% higher than that estimated from human images (4.8 µGy/MBq).…”

“…Subjects underwent both transmission and dynamic emission scans on a GE Advance tomograph (GE Healthcare, Waukesha, WI). Following injection of 709 ± 79 MBq of 11 C] (R)-rolipram, each subject was imaged in 7 contiguous 15-cm bed positions beginning at the head and continuing to the middle of the thigh, following the protocol described by Sprague et al [16].…”

Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction

“…Subjecting this intermediate to the adapted SAW conditions next afforded RO 20–1724 in 63% yield. This new route does not only decrease the step count significantly (previously reported: 7 steps), but, according to the report by the Audisio lab, also bears the potential to introduce short-lived isotopes through the use of labeled CO 2 in the last step …”

Rolipram Attenuates MK-801-Induced Deficits in Latent Inhibition.

“…Although brain levels of cAMP and rolipram binding were not measured in the present research, the attenuating effect of rolipram on NMDA-induced deficits in latent inhibition of cued fear conditioning is presumably due to an amplification of the cAMP-PKA signaling pathway through PDE4 inhibition in brain regions that support learning of the task. Studies devoted to examining rolipram binding in the brain (Kaulen, Bruning, Schneider, Sarter, & Baumgarten, 1989; Krause & Kuhne, 1988; Lourenco, DaSilva, Warsh, Wilson, & Houle, 1999; Lourenco et al, 2001; Randt et al, 1982; Schneider, Schmiechen, Brezinski, & Seidler, 1986) suggest that rolipram binds in a number of brain regions that may support latent inhibition learning, including the hippocampus (Han, Gallagher, & Holland, 1995; Kaye & Pearce, 1987; Oswald et al, 2002; Pouzet, Zhang, Weiner, Feldon, & Yee, 2004; Schmajuk, Christiansen, & Cox, 2000; Schmajuk, Lam, & Christiansen, 1994) and the amygdala (Coutureau, Blundell, & Killcross, 2001; Schauz & Koch, 2000). Lourenco et al (2001) demonstrated through competition studies that doses of rolipram as low as 0.05 mg/kg significantly reduce binding of radioactively labeled rolipram in a number of regions of the brain, including the hippocampus.…”

Whole-body biodistribution and radiation dosimetry in monkeys and humans of the phosphodiesterase 4 radioligand [11C](R)-rolipram: comparison of two-dimensional planar, bisected and quadrisected image analyses

“…Mean residence times were calculated based on the imaging data acquired from three different monkeys by using the weighting factor described in Materials and Methods to convert to human values ( Table 1). Based on these residence times, the organs with the highest radiation doses (µGy/MBq) were the urinary bladder wall (57), kidneys (26), liver (12), and lungs (11). The estimated human effective dose from the monkey 2D planar analysis was 6.6 µGy/MBq, which was 40% higher than that estimated from human images (4.8 µGy/MBq).…”

“…Subjects underwent both transmission and dynamic emission scans on a GE Advance tomograph (GE Healthcare, Waukesha, WI). Following injection of 709 ± 79 MBq of 11 C] (R)-rolipram, each subject was imaged in 7 contiguous 15-cm bed positions beginning at the head and continuing to the middle of the thigh, following the protocol described by Sprague et al [16].…”

Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction

“…Subjecting this intermediate to the adapted SAW conditions next afforded RO 20–1724 in 63% yield. This new route does not only decrease the step count significantly (previously reported: 7 steps), but, according to the report by the Audisio lab, also bears the potential to introduce short-lived isotopes through the use of labeled CO 2 in the last step …”

Rolipram Attenuates MK-801-Induced Deficits in Latent Inhibition.

“…Although brain levels of cAMP and rolipram binding were not measured in the present research, the attenuating effect of rolipram on NMDA-induced deficits in latent inhibition of cued fear conditioning is presumably due to an amplification of the cAMP-PKA signaling pathway through PDE4 inhibition in brain regions that support learning of the task. Studies devoted to examining rolipram binding in the brain (Kaulen, Bruning, Schneider, Sarter, & Baumgarten, 1989; Krause & Kuhne, 1988; Lourenco, DaSilva, Warsh, Wilson, & Houle, 1999; Lourenco et al, 2001; Randt et al, 1982; Schneider, Schmiechen, Brezinski, & Seidler, 1986) suggest that rolipram binds in a number of brain regions that may support latent inhibition learning, including the hippocampus (Han, Gallagher, & Holland, 1995; Kaye & Pearce, 1987; Oswald et al, 2002; Pouzet, Zhang, Weiner, Feldon, & Yee, 2004; Schmajuk, Christiansen, & Cox, 2000; Schmajuk, Lam, & Christiansen, 1994) and the amygdala (Coutureau, Blundell, & Killcross, 2001; Schauz & Koch, 2000). Lourenco et al (2001) demonstrated through competition studies that doses of rolipram as low as 0.05 mg/kg significantly reduce binding of radioactively labeled rolipram in a number of regions of the brain, including the hippocampus.…”

Whole-body biodistribution and radiation dosimetry in monkeys and humans of the phosphodiesterase 4 radioligand [11C](R)-rolipram: comparison of two-dimensional planar, bisected and quadrisected image analyses

“…Mean residence times were calculated based on the imaging data acquired from three different monkeys by using the weighting factor described in Materials and Methods to convert to human values ( Table 1). Based on these residence times, the organs with the highest radiation doses (µGy/MBq) were the urinary bladder wall (57), kidneys (26), liver (12), and lungs (11). The estimated human effective dose from the monkey 2D planar analysis was 6.6 µGy/MBq, which was 40% higher than that estimated from human images (4.8 µGy/MBq).…”

“…Subjects underwent both transmission and dynamic emission scans on a GE Advance tomograph (GE Healthcare, Waukesha, WI). Following injection of 709 ± 79 MBq of 11 C] (R)-rolipram, each subject was imaged in 7 contiguous 15-cm bed positions beginning at the head and continuing to the middle of the thigh, following the protocol described by Sprague et al [16].…”