TY - JOUR
T1 - Highly potent indanamine serotonin uptake blockers as radiotracers for imaging serotonin uptake sites
AU - Suehiro, Makiko
AU - Scheffel, Ursula A.
AU - Ravert, Hayden T.
AU - Ricaurte, George A.
AU - Hatzidimitriou, George
AU - Dannals, Robert F.
AU - Bøgesø, Klaus P.
AU - Wagner, Henry N.
N1 - Funding Information:
Acknowledgements-Thea uthors would like to thank MS Marigo Stathisa nd Mr StanleyK im for their skillful assistancew ith animal experimentsa, nd Mr Robert C. Smootf or his assistancwe ith thet runs-[“CIDBPI syntheses. Thev also thank Dr Bruce E. Marvanoff of the R. W. Johnson PharmaceuticaRl esearchI nstitutef or providing samples of McN5652-Z. This work was supported by USPHS grantsD A 06309a nd NS 15080.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1994/11
Y1 - 1994/11
N2 - Two highly potent indanamine serotonin (5-HT) uptake blockers, trans-3′-(4′-bromophenyl)-1-indanamine (trans-[11C]DBPI or [11C]Lu 19-056) and its iodo analog, trans-3′(4′-[125I]iodophenyl)-1-indanamine (trans-[125I]DIPI) were evaluated as radiotracers for imaging 5-HT uptake sites in vivo. Trans-[11C]DBPI was synthesized by N-methylation of the normethyl precursor with [11C]iodomethane. Trans-[125I]DIPI was synthesized by iododestannylation of the tributyltin precursor with [125I]NaI. Radiochemical yields for the [11C] and [125I] radiotracers were 34 and 40%, with specific activities of 4000 and 1800 mCi/μmol, respectively. In vitro, the iodo analog, trans-DIPI, showed an IC50 value of 0.26 nM in inhibition of [3H]paroxetine binding to 5-HT uptake sites in rat cortex. The potency was found to be equivalent to that of paroxetine or McN5652. In vivo, after i.v. injection into mice, both radiotracers showed high uptake in brain (3-4% dose/whole brain at 15 min) and high accumulation into target tissues such as hypothalamus and olfactory tubercles (7-8% dose/g at 60 min). The binding was blocked by pre-injection of 5 mg/kg of paroxetine. While the in vivo distribution agreed with previously reported 5-HT uptake site distribution, the radiotracers showed high uptake in non-target tissues such as cerebellum, resulting in low target-to-non-target ratios (1.5-1.6 at 60 min). Since washout from non-target regions was slower than from target regions, longer-time observation with 125I up to 6 h did not improve the ratios. HPLC analyses of mouse brain homogenates and blocking studies indicated that the high uptake in non-target regions is not the result of metabolism or any interaction of the radiotracers with those tissues via specific binding sites. In spite of low target-to-non-target ratios, target regions with high density of 5-HT uptake sites, such as the raphe nuclei, superior colliculi and substantia nigra, were visualized with trans-[125I]DIPI by ex vivo autoradiography, since the radiotracer showed high specific binding (total minus nonspecific binding).
AB - Two highly potent indanamine serotonin (5-HT) uptake blockers, trans-3′-(4′-bromophenyl)-1-indanamine (trans-[11C]DBPI or [11C]Lu 19-056) and its iodo analog, trans-3′(4′-[125I]iodophenyl)-1-indanamine (trans-[125I]DIPI) were evaluated as radiotracers for imaging 5-HT uptake sites in vivo. Trans-[11C]DBPI was synthesized by N-methylation of the normethyl precursor with [11C]iodomethane. Trans-[125I]DIPI was synthesized by iododestannylation of the tributyltin precursor with [125I]NaI. Radiochemical yields for the [11C] and [125I] radiotracers were 34 and 40%, with specific activities of 4000 and 1800 mCi/μmol, respectively. In vitro, the iodo analog, trans-DIPI, showed an IC50 value of 0.26 nM in inhibition of [3H]paroxetine binding to 5-HT uptake sites in rat cortex. The potency was found to be equivalent to that of paroxetine or McN5652. In vivo, after i.v. injection into mice, both radiotracers showed high uptake in brain (3-4% dose/whole brain at 15 min) and high accumulation into target tissues such as hypothalamus and olfactory tubercles (7-8% dose/g at 60 min). The binding was blocked by pre-injection of 5 mg/kg of paroxetine. While the in vivo distribution agreed with previously reported 5-HT uptake site distribution, the radiotracers showed high uptake in non-target tissues such as cerebellum, resulting in low target-to-non-target ratios (1.5-1.6 at 60 min). Since washout from non-target regions was slower than from target regions, longer-time observation with 125I up to 6 h did not improve the ratios. HPLC analyses of mouse brain homogenates and blocking studies indicated that the high uptake in non-target regions is not the result of metabolism or any interaction of the radiotracers with those tissues via specific binding sites. In spite of low target-to-non-target ratios, target regions with high density of 5-HT uptake sites, such as the raphe nuclei, superior colliculi and substantia nigra, were visualized with trans-[125I]DIPI by ex vivo autoradiography, since the radiotracer showed high specific binding (total minus nonspecific binding).
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U2 - 10.1016/0969-8051(94)90180-5
DO - 10.1016/0969-8051(94)90180-5
M3 - Article
C2 - 9234366
AN - SCOPUS:0028641210
SN - 0969-8051
VL - 21
SP - 1083
EP - 1091
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 8
ER -