Raclopride C 11 (Systemic)


VA CLASSIFICATION
Primary: DX201

Another commonly used name is
[ O-methyl- 11C]raclopride .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Diagnostic aid, radioactive (brain disease)—

Indications

Note: Because raclopride C 11 is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this product.


Accepted

—[Brain imaging, positron emission tomographic]1—Raclopride C 11 is used with positron emission tomography (PET) as a clinical research tool to determine dopamine type 2 (D 2) receptor density in the human brain under normal and pathological conditions {04} {07} {16} {19} {23} {24} {28} {33} {34} {36}.
—For example, raclopride C 11 used in PET studies has served to confirm the age-related decrease in striatal dopamine D 2 receptor density, which may be associated with a decline in motor as well as cognitive functions {20} {27} {29} {33}.
—Raclopride C 11 with PET has been used to investigate various disorders involving dopamine deficiency. For instance, studies in symptomatic and asymptomatic carriers of the dopa-responsive dystonia (DRD) gene have shown increased striatal D 2 receptor binding of raclopride C 11 in the asymptomatic subjects {28}. These findings suggest that the asymptomatic DRD gene carriers have increased numbers of D 2 receptors in the striatum that may help protect them from the clinical manifestations of dopamine deficiency {28}.
—In patients with Alzheimer's disease, raclopride C 11 may be used to examine neuroreceptor distribution and quantities, which may help in the analysis of degenerative alterations of neuron populations and neuroreceptor systems in patients with this disease {07}.
—Raclopride C 11 with PET may be useful for investigating the dopaminergic function in the striatum as a means of differentiating patients with multiple system atrophy from patients with Parkinson's disease {23}. In addition, it may help categorize and predict clinical measures of disease severity in multiple system atrophy patients {23}.
— Dopamine D 2 receptor density has been assessed in patients with schizophrenia, including neuroleptic naive schizophrenics, using raclopride C 11 with PET {04}. Also, raclopride C 11 with PET has been used to evaluate the neocortical receptor occupancy of antipsychotic drugs used in the clinical treatment of patients with schizophrenia {08} {13} {16} {30}. A statistically significant relationship between the degree of selective D 2 receptor occupancy and the antipsychotic effects of these drugs was found in several studies {08} {13} {16}.
— In Huntington's disease, in which degeneration of neostriatal interneurons occurs (postsynaptic to the dopaminergic input), specific binding of raclopride C 11 to D 2 receptors may serve as one of the parameters in predicting performance in cognitive tasks {24}. Also, raclopride C 11 used in PET studies of asymptomatic carriers of the Huntington's disease mutation demonstrated significant reductions in striatal dopamine receptor binding in these subjects {21} {22}. Accordingly, raclopride C 11 may provide a means of detecting subclinical striatal dysfunction, and help in assessing the rate of progression of Huntington's disease {21} {22}.
—In addition, raclopride C 11 with PET may be used to evaluate the response to treatment of pituitary tumors, such as prolactinomas, with dopamine agonists (e.g., bromocriptine), and to predict the effect of such treatment {04}.

1 Not included in Canadian product labeling.



Physical Properties

Nuclear Data {04} {05}



Radionuclide
(half-life) 
Mode of
decay 
Principal
photon emissions
(keV) 
Mean number
of emissions/
disintegration 
C 11
(20.41 min) 
Positron
decay 
Annihilation*
(511) 
* The 2 annihilation photons emitted in opposite directions at the moment of positron annihilation are used for imaging purposes. Detection devices generally used are positron emission tomography (PET) units; however, conventional planar scintillation cameras equipped with coincidence circuitry or high-energy collimators have been used for some studies {04} {09}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—Raclopride, a compound of the salicylamide series, is an antipsychotic drug with high selectivity and affinity for central D 2-dopamine receptors {11} {12} {35}.

Source—Carbon C 11 ( 11CO 2) may be produced by the 14N(p,alpha) 11C nuclear reaction on a target of nitrogen gas {04}. 11CO 2 is used in the preparation of the reactive precursors 11C-iodomethane and 1- 11C-iodoethane {04}. Raclopride can be labeled with carbon-11 either by N-ethylation with 1- 11C-iodoethane or by O-methylation with 11C-iodomethane {04} {05} {10} {14}. Various methods for the synthesis of raclopride C 11 have been developed {04} {06} {09} {14} {25}.

Mechanism of action/Effect:

The radioligand raclopride C 11 is retained in tissue as a result of binding to a neurotransmitter receptor {04} {11}. Raclopride is a selective dopamine antagonist with a high affinity for dopamine type 2 (D 2) receptors {04} {07} {09} {11} {16} {33} {35}. Since the neurotransmitter dopamine may be involved in various neuropsychiatric diseases, the in vivo binding of raclopride to dopamine receptors in the striatum can be measured by positron emission tomography (PET) with radiolabeled raclopride used as a tracer {07} {21} {22} {33} {35} {37}.

Distribution:

Raclopride C 11 is rapidly cleared from both plasma and whole blood, and crosses the blood-brain barrier {04} {11}. After intravenous administration, raclopride C 11 localizes in the basal ganglia, a region with a high density of dopamine receptors {10} {11} {19}. PET images show stereoselective concentration of raclopride C 11 in the region of the putamen relative to the rest of the brain {10} {36}.

PET images of the corpus striatum represent high binding to D 2 receptors {17} {18} {20} {33} {35} {36}. The cerebellum has virtually no dopamine D 2 receptors {24} {31}; therefore, the accumulation of raclopride C 11 in the cerebellum serves as a measure of nonspecific or nonreceptor-associated binding {24} {25} {31} {35}. Very little nonspecific binding of raclopride occurs {11} {24}.

Time to peak diagnostic effect

Time to imaging—Immediately after injection {20} {25} {27}, and continued for approximately 60 minutes {07} {20} {25} {27}.

Radiation dosimetry:


Dynamic emission scans obtained over 2 hours after injection of raclopride C 11 in three rhesus monkeys showed early accumulation of activity in the liver and kidneys, with activity in the gallbladder increasing rapidly at about 20 minutes{40} . Dose estimates were calculated by fitting exponential functions to the data (extrapolated to humans). The critical organ was the gallbladder with an estimated radiation dose of 0.061 milligray per megabecquerel (mGy/MBq) (224 millirad per millicurie [mrad/mCi]). Estimated doses for other organs included: liver 0.032 mGy/MBq (117 mrad/mCi), urinary bladder wall 0.017 mGy/MBq (63 mrad/mCi), small intestine 0.016 mGy/MBq (60 mrad/mCi), and kidney 0.009 mGy/MBq (34 mrad/mCi){40} . The effective dose equivalent was 0.01 millisievert/MBq (37 millirem/mCi){40}

Elimination:
    Biliary {40}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies to assess transplacental transfer of raclopride C 11 have not been done in humans. The possibility of pregnancy should be assessed in women of childbearing potential. Clinical situations exist where the benefits to the patient and fetus, based on information derived from radiopharmaceutical use, outweigh the risks from fetal exposure to radiation. In this situation, the physician should use discretion and reduce the administered activity to the lowest practical amount. {01}

Breast-feeding

It is not known whether raclopride C 11 is distributed into breast milk. However, due to the short physical half-life of raclopride C 11, any excretion of this agent during lactation is unlikely to result in significant radiation exposure to the breast-feeding infant. The absorbed radiation dose to the breast-feeding infant will be negligible after waiting 2 hours {32}.

Pediatrics

Appropriate studies on the relationship of age to the effects of raclopride C 11 have not been performed in children. However, pediatrics-specific problems that would limit the usefulness of raclopride C 11 in children are not expected.


Geriatrics


Appropriate studies on the relationship of age to the effects of raclopride C 11 have not been performed in the geriatric population. However, studies that included older patients were conducted, and geriatrics-specific problems that would limit the usefulness of this agent in the elderly are not expected {20} {27} {29}. Age has been reported to correlate negatively with specific raclopride C 11 binding {20} {27} {29}. In one study, with volunteers ranging in age from 24 to 73 years, the binding to the dopamine D2 receptors declined with age at an estimated rate of 7.9% per decade {20}. This decline in raclopride C 11 binding may be due to an age-related decrease in the number of receptors and in cerebral blood flow {07}. Significant age-related decreases occur relatively early in life (40 years of age) {20}.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Prolactin, serum{09}{12}{34}     (although not likely to occur with the administration of raclopride C 11 for diagnostic purposes, administration of non-radioactive raclopride in doses up to 4 mg twice daily has been reported to induce a rapid and transient increase of serum prolactin concentrations in both males and females {09} {12} {34})


Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With results of this test

Due to other medications
Dopamine (D 2) receptor-blocking medications, such as:
Clozapine
Haloperidol
Phenothiazines    (prior administration of these medications may reduce the number of available dopamine D 2 receptors; therefore, raclopride C 11 binding may be decreased {34} {35} {37} {38} {39}. Clozapine has been shown to have a lower D 2 receptor occupancy than the classical neuroleptics; thus, raclopride C 11 binding would be less affected with clozapine than with other neuroleptics {16} {39})


Ketamine{25}    (may decrease raclopride C 11 binding as a result of increased striatal dopamine concentrations {25})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problem exists
Sensitivity to the radiopharmaceutical preparation


Side/Adverse Effects
Although not likely to occur with the administration of raclopride C 11 for diagnostic purposes (usually less than 1 or 2 micrograms, total mass), administration of therapeutic doses of non-radioactive raclopride has been reported to induce akathisia and extrapyramidal effects {09} {12} {13} {15} {16} {34}. The severity and duration of these effects appear to be dose-related {09} {12} {13} {15} {34}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Radiopharmaceuticals (Diagnostic) .
In providing consultation, consider emphasizing the following selected information (>> = major clinical significance):

Description of use
Action in the body: Uptake of radioactivity in dopamine D 2 receptors may be visualized by external imaging

Small amounts of radioactivity used in diagnosis; radiation received is low and considered safe

Before having this test
»   Conditions affecting use, especially:
Sensitivity to the radiopharmaceutical preparation

Pregnancy—Risk to fetus from radiation exposure as opposed to benefit derived from use should be considered

Preparation for this test
Nuclear medicine department should advise patient on any preparatory instructions

Precautions after having this test
No special precautions needed


General Dosing Information
Radiopharmaceuticals are to be administered only by or under the supervision of physicians who have had extensive training in the safe use and handling of radioactive materials and who are authorized by the appropriate federal or state regulatory agency, if required, or, outside the U.S., the appropriate authority {02}.

Safety considerations for handling this radiopharmaceutical
Guidelines for the receipt, storage, handling, dispensing, and disposal of radioactive materials are available from scientific, professional, state, federal, and international bodies. Handling of this radiopharmaceutical should be limited to those individuals who are appropriately qualified and authorized. {03}


Parenteral Dosage Forms

RACLOPRIDE C 11 INJECTION USP

Note: Because raclopride C 11 is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this product.


Usual adult administered activity
[Brain imaging]1
Intravenous, 110 to 496 megabecquerels (3 to 13.4 millicuries), with specific radioactivity between 18.5 and 55.5 megabecquerels (0.5 and 1.5 millicuries), administered as a bolus injection {07} {13} {16} {20} {25} {31} {34}.


Note: Striatal uptake and image contrast depend on the mass of raclopride C 11 {04}. At high specific activity, specific binding is much greater than nonspecific uptake, and maximum image contrast between the striatum and cerebellum is obtained {04}. For optimal efficacy in measuring receptor densities, the specific activity of raclopride C 11 should not be less than 18.5 gigabecquerels (500 millicuries) per micromole at the time of calibration {04} {05}.


Usual pediatric administered activity
Safety and efficacy have not been established.

Usual geriatric administered activity
See Usual adult administered activity.

Strength(s) usually available
U.S.—
Prepared on-site at various clinical facilities.

Canada—
Prepared on-site at various clinical facilities.

Packaging and storage:
Unless otherwise specified by the supplier, it is prudent to avoid extreme temperatures {09}.

Stability:
Preparations of raclopride C 11 (5 gigabecquerels per micromole) have been shown to be stable at room temperature for 74 minutes {04} {14}.


Caution:
Radioactive material.



Developed: 06/15/1999



References
  1. Radiopharmaceuticals Advisory Panel Meeting, 5/91.
  1. Radiopharmaceuticals Advisory Panel Meeting, 8/92.
  1. Radiopharmaceuticals Advisory Panel Meeting, 4/96.
  1. Stöcklin G, Pike VW, editors. Radiopharmaceuticals for positron emission tomography: methodological aspects. Boston: Kluwer Academic Publishers; 1993. p. 115-7.
  1. The United States pharmacopeia. The national formulary. USP 23rd revision (January 1, 1995). NF 18th ed. (January 1, 1995). Rockville, MD: The United States Pharmacopeial Convention Inc; 1994 (Sixth Supplement, 1997). p. 3659.
  1. Ehrin E, Farde L, de Paulis T, et al. Preparation of 11C-labelled raclopride, a new potent dopamine receptor antagonist: preliminary PET studies of cerebral dopamine receptors in the monkey. Int J Appl Radiat Isot 1985 Apr; 36(4): 269-73.
  1. Sedvall G, Nybäck H, Farde L, et al. Neurotransmitter receptor imaging in Alzheimer's disease. J Neural Tansm 1987; 24(Suppl): 43-8.
  1. Farde L, Wiesel FA, Halldin C, et al. Central D 2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 1988 Jan; 45(1): 71-6.
  1. Farde L, Wiesel FA, Jansson P, et al. An open label trial of raclopride in acute schizophrenia: confirmation of D 2-dopamine receptor occupancy by PET. Psychopharmacology (Berl) 1988; 94(1): 1-7.
  1. Farde L, Pauli S, Hall H, et al. Stereoselective binding of 11C-raclopride in living human brain-a search for extrastriatal central D 2-dopamine receptors by PET. Psychopharmacology (Berl) 1988; 94(4): 471-8.
  1. Hall H, Kohler C, Gawell L, et al. Raclopride, a new selective ligand for the dopamine-D 2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 1988; 12(5): 559-68.
  1. Farde L, von Bahr C, Wahlen A, et al. The new selective D 2-dopamine receptor antagonist raclopride-pharmacokinetics, safety and tolerability in healthy males. Int Clin Psychopharmacol 1989 Apr; 4(2): 115-26.
  1. Wiesel FA, Farde L, Halldin C. Clinical melperone treatment blocks D 2-dopamine receptors in the human brain as determined by PET. Acta Psychiatr Scand 1989; (352): 30-4.
  1. Pike VW, Kensett MJ, Turton DR, et al. Labelled agents for PET studies of the dopaminergic system-some quality assurance methods, experience and issues. Int J Rad Appl Instrum [A] 1990; 41(5): 483-92.
  1. Farde L. Selective D 1- and D 2-dopamine receptor blockade both induces akathisia in humans: a PET study with [ 11C]SCH 23390 and [ 11C]raclopride. Psychopharmacology (Berl) 1992; 107(1): 23-9.
  1. Nordström AL, Farde L, Wiesel FA, et al. Central D 2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 1993 Feb 15; 33(4): 227-35.
  1. Mohell N, Sallemark M, Rosqvist S, et al. Binding characteristics of remoxipride and its metabolites to dopamine D 2 and D 3 receptors. Eur J Pharmacol 1993 Jul; 238(1): 121-5.
  1. Seeman P, Guan HC, Van Tol HH, et al. Low density of dopamine D 4 receptors in Parkinson's, schizophrenia, and control brain striata. Synapse 1993 Aug; 14(4): 247-53.
  1. Farde L, Hall H, Pauli S, et al. Variability in D 2-dopamine receptor density and affinity: a PET study with [ 11C]raclopride in man. Synapse 1995 Jul; 20(3): 200-8.
  1. Volkow ND, Wang GJ, Fowler JS, et al. Measuring age-related changes in dopamine D 2 receptors with 11C-raclopride and 18F- N-methylspiroperidol. Psychiatry Res 1996 May 31; 67(1): 11-6.
  1. Weeks RA, Piccini P, Harding AE, et al. Striatal D 1 and D 2 dopamine receptor loss in asymptomatic mutation carriers of Huntington's disease. Ann Neurol 1996 Jul; 40(1): 49-54.
  1. Antonini A, Leenders KL, Spiegel R, et al. Striatal glucose metabolism and dopamine D 2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease. Brain 1996 Dec; 119(Pt 6): 2085-95.
  1. Antonini A, Leenders KL, Vontobel P, et al. Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson's disease. Brain 1997 Dec; 120(Pt 12): 2187-95.
  1. Bäckman L, Robins-Wahlin TB, Lundin A, et al. Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes. Brain 1997 Dec; 120(Pt 12): 2207-17.
  1. Smith GS, Schloesser R, Brodie JD, et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology 1998 Jan; 18(1): 18-25.
  1. Antonini A, Leenders KL, Eidelberg D. [ 11C]raclopride-PET studies of the Huntington's disease rate of progression: relevance of the trinucleotide repeat length. Ann Neurol 1998 Feb; 43(2): 253-5.
  1. Volkow ND, Gur RC, Wang GJ, et al. Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am J Psychiatry 1998 Mar; 155(3): 344-9.
  1. Kishore A, Nygaard TG, de la Fuente-Fernandez R, et al. Striatal D 2 receptors in symptomatic and asymptomatic carriers of dopa-responsive dystonia measured with [ 11C]-raclopride and positron-emission tomography. Neurology 1998 Apr; 50(4): 1028-32.
  1. Pohjalainen T, Rinne JO, Nagren K, et al. Sex differences in the striatal dopamine D 2 receptor binding characteristics in vivo. Am J Psychiatry 1998 Jun; 155(6): 768-73.
  1. Hagberg G, Gefvert O, Bergström M, et al. N-[ 11C]methylspiperone PET, in contrast to [ 11C]raclopride, fails to detect D 2 receptor occupancy by an atypical neuroleptic. Psychiatry Res 1998 Jun 30; 82(3): 147-60.
  1. Ito H, Hietala J, Blomqvist G, et al. Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [ 11C]raclopride binding. J Cereb Blood Flow Metab 1998 Sep; 18(9): 941-50.
  1. Radiopharmaceuticals Advisory Panel Meeting, 10/98.
  1. Volkow ND, Fowler JS, Gatley SJ, et al. PET evaluation of the dopamine system of the human brain. J Nucl Med 1996 Jul; 37(7): 1242-56.
  1. Reviewers' comments on monograph revision of 3/22/99.
  1. Farde L, Ehrin E, Eriksson L, et al. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 1985 Jun; 82(11): 3863-7.
  1. Farde L, Hall H, Ehrin E, et al. Quantitative analysis of D 2 dopamine receptor binding in the living human brain by PET. Science 1986 Jan 17; 231(4735): 258-61.
  1. Farde L, Halldin C, Stone-Elander S, et al. PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride. Psychopharmacology (Berl) 1987; 92(3): 278-84.
  1. Farde L, Nordström AL, Wiesel FA, et al. Positron emission tomographic analysis of central D 1 and D 2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry 1992 Jul; 49(7): 538-44.
  1. Farde L, Nordström AL, Nyberg S, et al. D 1, D 2, and 5-HT2-receptor occupancy in clozapine-treated patients. J Clin Psychiatry 1994 Sep; 55 Suppl B: 67-9.
  1. Herscovitch P, Schmall B, Doudet DJ, et al. Biodistribution and radiation dose estimates for [C 11]raclopride. In: Proceedings of the 44th annual meeting of the Society of Nuclear Medicine. J Nucl Med 1997; 38: 224P.
Hide
(web4)