Carroll D. Arnett

Turnover of brain monoamine oxidase measured in vivo by positron emission tomography using L-[11C]deprenyl.

The distribution of carbon‐11‐labeled L‐deprenyl, an irreversible inhibitor of monoamine oxidase type B (MAO‐B), was determined in the baboon brain by positron emission tomography. The irreversible blood‐to‐brain transfer constant (influx constant, Ki) was measured using a complete metabolite‐corrected arterial plasma concentration curve. This influx constant was used as a measure of functional enzyme activity for sequential determinations of MAO‐B recovery following a single high dose of unlabeled l‐deprenyl. The half‐life for turnover of MAO‐B was thus determined to be 30 days. Using appropriate irreversible inhibitors, this procedure should be generally useful for determining enzyme turnover rates in any organ in vivo and can be applied to some human studies as well.

Comparison of three 18F-labeled butyrophenone neuroleptic drugs in the baboon using positron emission tomography

Abstract: The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine‐18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)‐butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4‐h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8‐h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

[18F]-N-methylspiroperidol: The radioligand of choice for pett studies of the dopamine receptor in human brain

N-Methylspiroperidol, the amide N-methyl analogue of the neuroleptic spiroperidol, was radiolabeled with fluorine-18, and its distribution in the baboon brain was studied using positron emission transaxial tomography. Stereospecific binding was demonstrated in the striatum (but not in the cerebellum) by pretreatment with (-)- or (+)-butaclamol. The kinetic distribution was similar to that of [18F]spiroperidol, but the absolute striatal uptake (in percent of administered dose) was at least two-fold higher. Analysis of baboon blood at 10 min after injection indicated that less than half of the radioactivity in the plasma was due to unchanged radioligand. Analysis of the metabolic stability of [18F]-N-methylspiroperidol in rat brain for 4 hr indicated that, like [18F]spiroperidol, it is very stable to metabolic transformation in the rat central nervous system. Striatal uptake and retention in the rat was five-fold higher for [18F]-N-methylspiroperidol than for [18F]spiroperidol. These results suggest that [18F]-N-methylspiroperidol is an ideal choice for studies of the dopamine receptor in humans.

Carbon-11 labelled ketamine—Synthesis, distribution in mice and PET studies in baboons

No-carrier-added (NCA)[11C](+/-)-ketamine (2a) and its enantiomers (+)-2b and (-)-2c were synthesized by methylation of the corresponding norketamine (1a-c) with [11C]H3I in an overall radiochemical yield of 20% (EOB) with specific activities of 0.35-0.45 Ci/mumol at EOB in a synthesis time of 40 min from EOB. Compound 2a was metabolized rapidly in mouse brain and labeled metabolites appeared in baboon plasma. PET studies of compounds 2a-c in a baboon showed that influx of compounds 2a-c into the brain was high for the first few min but radioactivity then declined rapidly. Although the retention of radioactivity in the baboon striatum was not significantly different for 2a-c 20 min post-injection, graphical analysis of time-activity data for each enantiomer and for the racemate in baboon striatum suggested that (+)-ketamine may interact with receptors slightly more effectively than its (-)-enantiomer or racemate. However, due to its rapid metabolism in the brain and a similar uptake in the striatum and cerebellum, [11C]ketamine may not be an ideal tracer for studying NMDA receptor with PET.

Species differences in [11C]clorgyline binding in brain.

[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.

A direct comparison of the brain uptake and plasma clearance of N-[11C]methylspiroperidol and [18f]N-methylspiroperidol in baboon using PET

Serial PET studies of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol were carried out in a single baboon with an intervening time period of 2 h between injection of the 11C and the 18F-labeled tracers. The kinetic patterns of uptake and egress of radioactivity in striatum and cerebellum as well as the magnitude of the uptake was very similar with the two tracers. In addition, no significant difference in clearance of total radioactivity from arterial plasma was detected. Analysis of plasma radioactivity for unchanged drug showed no significant differences in the amount of unchanged tracer at different times, although the profile of labeled metabolites was different. These results indicate that the only significant difference between the use of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol for PET studies of brain dopamine receptors relate to the difference in physical half-life of the radionuclide rather than to differences in the profile of metabolically produced labeled compounds.

A comparison of the brain uptake of N-(cyclopropyl[11C]methyl)norbuprenorphine ([11C]buprenorphine) and N-(cyclopropyl[11C]methyl)nordiprenorphme ([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.

Synthesis of 2-deoxy-2[82Br]bromo-d-mannose and related compounds and their biodistributions in mice

The synthesis of 2-deoxy-2-[82Br]bromo-3,4,6-tri-O-acetyl-α-d-mannopyranosyl chloride (compound 3b) and 2-deoxy-2-[82Br]bromo-d-mannose (compound 4d), and their biodistributions in mice are described. The reaction of 3,4,6-tri-O-acetyl-d-glucal (compound 2) with unlabeled and labeled bromine chloride (compounds 1a and 1b) generated in situ from the oxidation of bromide with N-chlorosuccinimide gave unlabeled and labeled 2-deoxy-2-bromo-3,4,6-tri-O-acetyl-α-d-mannopyranosyl chloride (compounds 3a and 3b) with a radiochemical yield of 58% (chemical yield, 63%). The hydrolysis of compounds 3a and 3b with 2N HCl gave 2-deoxy-2-bromo-d-mannose (compounds 4a and 4b) with a radiochemical yield of 72%. The biodistribution of compounds 3b and 4b after injection in mice indicated that 2% of the total injected radioactivity rapidly accumulated in the brain, while 6% of the total injected radioactivity accumulated in the heart; however, the radioactivity started to decline in these two organs after 15 min.

Synthesis and biodistribution of 2-deoxy-2-[18F] fluoro-D-glucopyranosyl [18F] fluoride in mice

AbstractThe synthesis and biodistribution of 2-deoxy-2-[18F]fluro-d-glucopyranosyl [18F]fluoride