Whole-Body Biodistribution and Radiation Dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A Novel Vesicular Monoamine Transporter 2 Imaging Agent

Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-18F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (18F-FP-(+)-dihydrotetrabenazine [DTBZ] or 18F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use. Methods: Nine healthy human subjects (mean age ± SD, 58.6 ± 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 ± 22.9 MBq of 18F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs. Results: The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% ± 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 ± 23.8 μGy/MBq, was the pancreas. The effective dose equivalent and effective dose for 18F-AV-133 were 36.5 ± 2.8 and 27.8 ± 2.5 μSv/MBq, respectively. These values are comparable to those reported for any other 18F-labeled radiopharmaceutical. Conclusion: 18F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.

[1]  T. Yen,et al.  Binding characteristics of 9-fluoropropyl-(+)-dihydrotetrabenzazine (AV-133) to the vesicular monoamine transporter type 2 in rats. , 2010, Nuclear medicine and biology.

[2]  Klaus Tatsch,et al.  Can SPET imaging of dopamine uptake sites replace PET imaging in Parkinson’s disease? , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[3]  J. Vennart.  Limits for intakes of radionuclides by workers: ICRP Publication 30. , 1981, Health physics.

[4]  Icrp.  1990 Recommendations of the International Commission on Radiological Protection , 1991 .

[5]  H. Kung,et al.  Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters. , 2007, Nuclear medicine and biology.

[6]  J. Mann,et al.  Whole body [11C]-dihydrotetrabenazine imaging of baboons: biodistribution and human radiation dosimetry estimates , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[7]  S. Gilman,et al.  Differentiating Alzheimer’s disease from dementia with Lewy bodies and Parkinson’s disease with (+)-[11C]dihydrotetrabenazine positron emission tomography , 2008, Alzheimer's & Dementia.

[8]  N. Bohnen,et al.  Positron Emission Tomography of Monoaminergic Vesicular Binding in Aging and Parkinson Disease , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  Thomas E. Nichols,et al.  Increased ventral striatal monoaminergic innervation in Tourette syndrome , 2003, Neurology.

[10]  Lisa Kuramoto,et al.  Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis. , 2004, Archives of neurology.

[11]  H. Kung,et al.  Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters. , 2006, Nuclear medicine and biology.

[12]  R. Albin,et al.  Striatal monoaminergic terminals in Lewy body and Alzheimer's dementias , 2002, Annals of neurology.

[13]  S. Gilman,et al.  Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging , 1996, Annals of neurology.

[14]  J. Valentin.  Basic anatomical and physiological data for use in radiological protection: reference values , 2002, Annals of the ICRP.

[15]  H. Kung,et al.  Pharmacokinetics of [(18)F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain. , 2007, Nuclear medicine and biology.

[16]  K. Frey,et al.  Effects of dopaminergic drug treatments on in vivo radioligand binding to brain vesicular monoamine transporters. , 1996, Nuclear medicine and biology.

[17]  L. Eiden,et al.  Chemical neuroanatomy of the vesicular amine transporters , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  R A Koeppe,et al.  Imaging the vesicular monoamine transporter. , 2001, Advances in neurology.

[19]  G. Klöppel,et al.  Expression of the Two Isoforms of the Vesicular Monoamine Transporter (VMAT1 and VMAT2) in the Endocrine Pancreas and Pancreatic Endocrine Tumors , 2003, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[20]  A. Stoessl,et al.  Dopamine receptors in Parkinson's disease: imaging studies. , 2003, Advances in neurology.

[21]  C. Rowe,et al.  In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with 18F-AV-133 , 2010, Journal of Nuclear Medicine.

[22]  T. Yen,et al.  Whole-body biodistribution and brain PET imaging with [18F]AV-45, a novel amyloid imaging agent--a pilot study. , 2010, Nuclear medicine and biology.

[23]  Luc Mortelmans,et al.  Dual-tracer dopamine transporter and perfusion SPECT in differential diagnosis of parkinsonism using template-based discriminant analysis. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[24]  A. Alavi,et al.  Binding of [99mTc]TRODAT-1 to dopamine transporters in patients with Parkinson's disease and in healthy volunteers. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[25]  M. Kilbourn,et al.  Rapid and differential losses of in vivo dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) radioligand binding in MPTP‐treated mice , 2000, Synapse.

[26]  H. Watabe,et al.  Absorbed dose estimates in positron emission tomography studies based on the administration of 18F-labeled radiopharmaceuticals. , 1991, Journal of radiation research.

[27]  M. Roberts,et al.  The pharmacokinetics of tetrabenazine and its hydroxy metabolite in patients treated for involuntary movement disorders , 2004, European Journal of Clinical Pharmacology.

[28]  M. Kilbourn.  In vivo radiotracers for vesicular neurotransmitter transporters. , 1997, Nuclear medicine and biology.

[29]  Michael G Stabin,et al.  OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[30]  D. Skovronsky,et al.  In Vivo Imaging of β-Cell Mass in Rats Using 18F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus , 2008, Journal of Nuclear Medicine.

[31]  R. Mehvar,et al.  Pharmacokinetics of tetrabenazine and its major metabolite in man and rat. Bioavailability and dose dependency studies. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[32]  D. Grosset,et al.  The role of radiotracer imaging in Parkinson disease , 2005, Neurology.

[33]  R. Albin,et al.  Rapid loss of striatal VMAT2 binding associated with onset of Lewy body dementia , 2006, Movement disorders : official journal of the Movement Disorder Society.

[34]  Herbert Malamud,et al.  MIRD Primer for Absorbed Dose Calculations , 1989 .

[35]  A. Luxen,et al.  PET radiopharmaceuticals in Europe: Current use and data relevant for the formulation of summaries of product characteristics (SPCs) , 1995, European Journal of Nuclear Medicine.