The syntheses of no‐carrier‐added and carrier‐added ¹⁸F‐labelled haloperidol

Abstract

ABWRACT 18Fluorine-18 labelled haloperidol ( F-HP) was synthesized by a fluorine-fluorine exchange reaction 078haloperidol, fluorinechlorine exchange on a chloro-analog of haloperidd, and from F-labelled pfluorobenzonitrile prepared by two dfferent exchange reactions. Nudeophilic fluorine was used in the form of tetra n-butyiammonium fluoride. The overall radiochemical yield, expessed at the end of syntheses UQS % for exchange in haloperidol and about 2%-3% for exchange in chloroanalog in a 40 min synthesis (from the end of the irmdiation). Specific activity up to 1 Ci/mmol for haloperidd and q to 5000 Ci/mmol for chlorwmalog as substrates were obtained. The syntheses ming psubstituted chloro-and nitro-benmnitriles as starting materials for t h e exchange reaction gave a product with an average specific activity of a tt 2000 Ci/mmol and in general an overall radiochemical yield of %-la. krification 02 F@operidoI was done by HPLC on aC-18 column. The radiochemical purity as assessed by t h n layer radiochromatography (TLRC) of t h e final ~o d u~t was at least 95%, with high chemical p i t y . Postmortem studies dare on human brain tissue have indicated a change in t h e concentration of dopaminergic receptor sites i n several diseases. (Changes i n Parkinsods disease (6) and schizophrenia (7) are of relevance to this paper.) However, s i t r e t h e tissue analyses were carried cut after the death of t h e patient, changes in the c o r r m t m t i o n of * Presentrd in part at the 187th Meeting of ACS, St. Lcuis, MO., April 8-13, 1984 (NUCL-60) and 5th Lnt. Symp. Radiopharm. Chem., Tokyo, Japan, July 9-13,1984. Towhan correspmderreshculd be addressed. KEY WORDS:

Structure–Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor

“…Variation of the p-fluorophenyl moiety of 1. To investigate positional effects of fluorine substitution on the butyrophenone phenyl ring on the kinetics of 1, we generated analogues with all possible mono and di-fluoro substituents (2-F (14a); 42 3-F (14b); 42 2,3-diF (14c); 2,4-diF (14d); 2,5-diF (14e); 2,6-diF (14f); 3,4-diF (14g); 42 3,5-diF (14h), as well as two ortho-substituted analogues (2-Cl (14i) and 2-Me (14j)), a para-substituted analogue (4-Cl (16k)) 43 and a des-fluoro variant (14l). 41 As detailed in scheme 3, commercially available 3-butynol (9) was treated with SOCl 2 and catalytic pyridine at reflux temperature, followed by distillation to afford 4-chlorobut-1-yne (10).…”

“…The etherand thioether-variants of 1 were accessed using a literature procedure in three steps 45 (17a-b, Figure 3, Supplementary Scheme 1), whilst the corresponding secondary alcohol was afforded in two-steps also through literature procedure (18, Figure 3) 46 (Supplementary Scheme 2). analogues 45 (17a-b, respectively); racemic alcohol analogue 46 (18) ; tropanyl analogue 34 (42); 9 piperazinyl analogue 34 (43); phenyl-and p-chlorophenylpiperidine analogues 38,47 (47-48, respectively); reverse substitution analogue 48 (53) ; des-halo analogue 41 (54).…”

“…53 was synthesised according to a literature procedure following Friedel-Crafts acylation and N-alkylation (Figure 3, Supplementary Scheme 6). 43 Compound 54 was similarly accessed through literature methods (Figure 3, Supplementary Scheme 7). 41 Pharmacology.…”

Radioligands for the dopamine receptor subtypes

“…This labeling reaction was performed in dimethyl sulfoxide as a solvent, resulting in an RCY of about 10% and a specific activity of only 185–370 GBq/mmol (5–10 Ci/mmol) . For both, [ 18 F]SP and [ 18 F]HP, the use of the corresponding nitro or chloro precursor for a single‐step radiosynthesis was reported, which led to a significantly increased specific activity of the final product (44 GBq/µmol) . A further improved specific activity for [ 18 F]SP and [ 18 F]HP was achieved by a three‐step radiosynthesis via [ 18 F]fluorobenzonitrile (Table ) .…”

Radiohalogen incorporation into organic systems

“…The low specific activity when haloperidol itself is used is probably a reflection of the isotopic dilution which inevitably results. 44 As an aside, there are in fact two aryl chlorine systems in the chloroanalogue of haloperidol. Both have p-substituents, but only the one with an electron-withdrawing acyl substituent undergoes halogen exchange.…”