Synthesis and biological evaluation of technetium(III) mixed-ligand complexes with high affinity for the cerebral 5-HT(1A) receptor and the alpha1-adrenergic receptor.
Tc(III) and Re(III) complexes [M(NS(3))(CNR)] (M = Re, 99mTc, NS(3) = 2,2',2"-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT(1A) as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the 99mTc complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one 99mTc representative in sections of post mortem human brain indicate its accumulation in 5-HT(1A) receptor-rich brain regions. However, addition of the specific 5-HT(1A) receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake.
Drews
A
A
Forschungszentrum Rossendorf, Institut für Bioanorganische und Radiopharmazeutische Chemie, Dresden, Germany.
Pietzsch
H-J
HJ
Syhre
R
R
Seifert
S
S
Varnäs
K
K
Hall
H
H
Halldin
C
C
Kraus
W
W
Karlsson
P
P
Johnsson
C
C
Spies
H
H
Johannsen
B
B
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002102:Cadaver; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011868:Radioisotopes / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D011920:Rats, Inbred WF; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D015203:Reproducibility of Results; D012211:Rhenium / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D013667:Technetium / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D010879:Piperazines; D011725:Pyridines; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D012211:Rhenium; D013667:Technetium