A comparison of the brain uptake of N-(cyclopropyl[11C]methyl)norbuprenorphine ([11C]buprenorphine) and N-(cyclopropyl[11C]methyl)nordiprenorphine ([11C]diprenorphine) in baboon using PET.

Buprenorphine and diprenorphine were radiolabeled with 11C and their distributions in the baboon brain were studied using positron emission tomography (PET). Specific binding was demonstrated in the striatum (but not in the cerebellum) by pretreating the baboon with (-)naloxone. The absolute striatal uptakes and time courses were similar for these two radioligands but the ratio of radioactivity in the striatum to cerebellum in the baboon was higher for [11C]diprenorphine than for [11C]buprenorphine. Analysis of baboon plasma indicated that both [11C]diprenorphine and [11C]buprenorphine are rapidly metabolized. Analysis of radioactivity in mouse brain indicated that these two radioligands are stable to metabolic transformation. At 30 min after injection, 86-90% of extracted radioactivity was due to unchanged 11C-labeled radioligands. These results suggest that both [11C]diprenorphine and [11C]buprenorphine may be useful radioligands for studying opioid receptors in humans, although [11C]diprenorphine may be a better radioligand than [11C]buprenorphine for this purpose because of its more rapid clearance from the cerebellum.

No-carrier-added (NCA) N-(3-[18F]fluoropropyl)-N-norbuprenorphine and N-(3-[18F]fluoropropyl)-N-nordiprenorphine--synthesis, anatomical distribution in mice and rats, and tomographic studies in a baboon.

N-(3-Fluoropropyl)-N-norbuprenorphine (3a) and N-(3-fluoropropyl)-N-nordiprenorphine (4a) were synthesized by N-alkylation of norbuprenorphine (1) and nordiprenorphine (2) with 1-bromo-3-fluoropropane. The corresponding no-carrier-added (NCA) N-(3-[18F]fluoropropyl)-N-norbuprenorphine (3b) and N-(3-[18F]fluoropropyl)-N-nordiprenorphine (4b) were synthesized by N-alkylation of 1 and 2 with NCA 1-[18F]fluoro-3-iodopropane in a synthesis time of approximately 100 min from end of bombardment (EOB) with an overall radiochemical yield of approximately 15% (EOB) and a mass of 2-3 nmol. In vitro studies indicate that in the absence of sodium chloride, compounds 3a, 4a, N-propyl-N-norbuprenorphine (5), buprenorphine and diprenorphine are reasonably comparable in binding affinity for opioid receptors. In the presence of 100 mM sodium chloride, however, compounds 3a, 4a and 5, are clearly less potent than buprenorphine and diprenorphine. The anatomical distribution study of compound 3b in mice shows radioactivity accumulating in bone, indicating that in vivo defluorination may have occurred. Rat studies of both compounds 3b and 4b indicate the specific distribution of these two radioligands within certain cortical and subcortical regions of rat brain. However, the absolute uptake of compound 4b in rat brain was only half that of compound 3b. PET studies of 3b in a baboon revealed specific binding of compound 3b in striatum and cerebellum. At 1 h after injection, ratios of specific/non-specific binding of 3b in striatum and cerebellum of a baboon were 1.9 and 1.7 respectively.

The utility of 1-[18F]fluoro-3-iodopropane for the synthesis of certain dopamine D-1 and benzodiazepine receptor radioligands.

No-carrier-added (NCA) R(+)-7-chloro-8-hydroxy-3-(3'-[18F]fluoropropyl)-1-phenyl-2,3,4,5- tetrahydro-3-benzazepine (2b) (an analog of dopamine D-1 receptor ligand SCH 23390), ethyl 8-fluoro-5,6-dihydro-5-(3'-fluoropropyl)-6-oxo-4H- imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (4b) and 3'-[18F]fluoropropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (6b) (analogs of the benzodiazepine RO 15-1788) were synthesized by alkylation of the corresponding nor-compound with NCA 1-[18F]fluoro-3-iodopropane in 10-15% yield (EOB) in approximately 110 min and with a mass of 2-3 nmol. Compound 2 is less potent (approximately 12-14 times) than SCH 23390 in binding to rat striatal membranes in vitro. Compounds 2b, 4b and 6b exhibit no specific anatomical distribution to mouse brain. These results suggest that the substituent at position 3 of SCH 23390, and position 5 and carboxylate group of RO 15-1788 are critical determinants both of affinity and selectivity for receptor binding, and underscores the evaluation necessary when even minor changes (C1 to C3) are made in bioactive compounds.

No-carrier-added N-(3-[18F]fluoropropyl)spiroperidol: biodistribution in mice and tomographic studies in a baboon.

Two potential radioligands, no-carrier-added (NCA) N-(2-[18F]fluoroethyl)spiroperidol (3) and N-(3-[18F]fluoropropyl)spiroperidol (4) have been synthesized for PET imaging of dopamine receptors in humans. Compounds 3 and 4 were synthesized by N-alkylation of spiroperidol with NCA 1-bromo-2-[18F]-fluoroethane (2b), 1-[18F]fluoro-3-iodopropane (2c) and 1-bromo-3-[18F]fluoropropane (2d) respectively. The biodistribution of 4 in mice showed that the mouse brain uptake of radioactivity was similar to that of [18F]-N-methylspiroperidol (1.1% of the administered dose), but the activity in bone (femur) increased with time. The kinetic distribution of compound 4 in baboon brain was similar to that of [18F]-N-methylspiroperiodol, and the striatal accumulation of radioactivity was also blocked stereoselectively by butaclamol. The ratio of striatum to cerebellum radioactivities at 3 hr after injection was 5.9. Analysis of the metabolic stability of 4 in mouse brains for 1 hr indicated that, like [18F]-N-methylspiroperidol, it is relatively stable to metabolic transformation in the central nervous system. These results suggest that compound 4 may be a useful radioligand for PET studies of the dopamine receptor in humans.

No-carrier-added (NCA) (+/-)-N-(3-[18F]fluoropropyl)-N-normetazocine-synthesis and PET studies in a baboon.

No-carrier-added (NCA) (+/-)-N-(3-[18F]Fluoropropyl)-N-normetazocine (2) was synthesized by N-alkylation of (+/-)-N-normetazocine (1) with NCA 1-[18F]fluoro-3-iodopropane in an overall radiochemical yield of 10% (EOB) with a mass of 3.5 nmol in a synthesis time of 90 min from end of bombardment (EOB). PET studies of 2 in a baboon did not indicate specificity for opiate receptor sites alone: The activity declined rapidly in the striatum, the frontal cortex and the cerebellum. The baboon total arterial plasma radioactivity clearance was very rapid and the metabolism of compound 2 in plasma was also very rapid. These results suggest that compound 2 is not a suitable radioligand for imaging opiate receptors in the human brain by positron tomography.