Effect of lipophilicity on the pharmacokinetics of radiolabeled spiperone analogues
Several radiolabeled analogues of the butyrophenone neuroleptic spiperone exhibit in vivo localization in D/sub 2/ receptor-rich areas of the brain. A series of N-alkylated spiperone analogues and the corresponding p-brominated compounds were synthesized to ascertain the optimum structure for labeling with /sup 18/F or /sup 75/Br. In vivo studies indicated that all analogues had D/sub 2/ receptor-binding affinity within the same order of magnitude (IC/sub 50/=2.6 nM for SP and 3.9 nM for BPSP), whereas the lipophilicity varied greatly (log P=2.7 for SP and 5.2 for BPSP). In vivo studies in the rat using the radiobrominated analogues were done using compounds labeled with n.c.a. /sup 77/Br via in-situ oxidation by dichloramine-T or H/sub 2/O/sub 2//CH/sub 3/COOH. Alkylation of BSP was found to decrease the striatum-to-cerebellum concentration at 6 hr from 8.2 for BSP to 5.2 for BPSP. Unexpectedly, the cerebral uptake did not increase with log P, the striatal concentration dropping from 390% MBC for BSP to 85% MBC for BPSP. This contrasts with previous results for SP and MSP, where the brain uptake increases slightly with log P. Increasing lipophilicity increases blood faster than brain concentrations, and it is concluded that whereas N-alkylation may be beneficial for /sup 18/F-labeld neuroleptics, non-alkylated spiperone is the optimum labeling substrate for /sup 75/Br.
- Research Organization:
- Institut fur Chemie 1, Kernforschungsanlage Julich GmbH, FRG
- OSTI ID:
- 6869148
- Report Number(s):
- CONF-850611-
- Journal Information:
- J. Nucl. Med.; (United States), Vol. 26:5; Conference: 32. annual meeting of the Society of Nuclear Medicine, Houston, TX, USA, 2 Jun 1985
- Country of Publication:
- United States
- Language:
- English
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BROMINE 75
RADIOCHEMISTRY
UPTAKE
CEREBRUM
RADIOISOTOPE SCANNING
DOPAMINE
RECEPTORS
FLUORINE 18
SPIPERONE
LABELLING
STRUCTURE-ACTIVITY RELATIONSHIPS
ALKYLATION
BINDING ENERGY
BIOLOGICAL LOCALIZATION
CEREBELLUM
CHEMICAL PREPARATION
CHLORAMINES
IN VITRO
RADIOPHARMACEUTICALS
RATS
TIME DEPENDENCE
TRACER TECHNIQUES
AMINES
ANIMALS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-PLUS DECAY RADIOISOTOPES
BODY
BRAIN
BROMINE ISOTOPES
CARDIOTONICS
CARDIOVASCULAR AGENTS
CENTRAL NERVOUS SYSTEM
CHEMICAL REACTIONS
CHEMISTRY
COUNTING TECHNIQUES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
ENERGY
FLUORINE ISOTOPES
HOURS LIVING RADIOISOTOPES
HYDROXY COMPOUNDS
INTERMEDIATE MASS NUCLEI
ISOTOPE APPLICATIONS
ISOTOPES
LABELLED COMPOUNDS
LIGHT NUCLEI
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NEUROREGULATORS
NUCLEI
ODD-EVEN NUCLEI
ODD-ODD NUCLEI
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
PHENOLS
POLYPHENOLS
PROTEINS
RADIOISOTOPES
RODENTS
SYMPATHOMIMETICS
SYNTHESIS
VERTEBRATES
550601* - Medicine- Unsealed Radionuclides in Diagnostics