In vivo studies of the SERT-selective [18F]FPBM and VMAT2-selective [18F]AV-133 radiotracers in a rat model of Parkinson's disease.
BACKGROUND
The utility of [(18)F]FPBM [2-(2'-((dimethylamino)methyl)-4'-(3-[(18)F]-fluoropropoxy)phenylthio)benzenamine], a selective serotonin transporter (SERT) tracer, and [(18)F]AV-133 [(+)-2-Hydroxy-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine], a selective vesicular monoamine transporter 2 (VMAT2) tracer, were tested in the 6-hydroxydopamine (6-OHDA) unilateral lesioned rat model.


METHODS
Positron emission tomography (PET) imaging of three 6-OHDA unilateral lesioned male Sprague Dawley rats (Rats 1-3) were performed with [(18)F]FPBM and [(18)F]AV-133 to examine whether changes in SERT and VMAT2 binding, respectively, could be detected in the brain. The brains of the three rats were then removed and examined by in vitro autoradiography with [(18)F]FPBM and the dopamine transporter ligand, [(125)I]IPT [N-(3'-[(125)I]-iodopropen-2'-yl)-2-beta-carbomethoxy-3-beta-(4-chloro phenyl) tropane, for confirmation. Biodistribution of [(18)F]FPBM in a separate group of p-chloroamphetamine (PCA) treated rats were also performed.


RESULTS
PET image analysis showed varying levels of SERT binding reduction (Rat 1=-11%, Rat 2=-4%, Rat 3=-43%; n=2) and a clear and definitive loss of VMAT2 binding (Rat 1=-87%, Rat 2=-72%, and Rat 3=-91%; n=1) in the left striatum when compared to the right (non-lesioned side) striatum. The results from PET imaging were corroborated with quantitative in vitro autoradiography. Rats treated with a selective serotonin toxin (p-chloroamphetamine) showed a significant reduction of [(18)F]FPBM uptake in the cortex and hypothalamus regions of the brain.


CONCLUSIONS
The preliminary data suggest that [(18)F]FPBM and [(18)F]AV-133 may be useful for the examination of serotonergic and dopaminergic neuron integrity, respectively, in the living brain.
Wang
Julie L
JL
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Oya
Shunichi
S
Parhi
Ajit K
AK
Lieberman
Brian P
BP
Ploessl
Karl
K
Hou
Catherine
C
Kung
Hank F
HF
D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes; D008297:Male; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*; D010133:p-Chloroamphetamine / Q000494:pharmacology / Q000627:therapeutic use
C527727:2-(2-((dimethylamino)methyl)-4-(3-fluoropropoxy)phenylthio)benzenamine; D000814:Aniline Compounds; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; D050486:Serotonin Plasma Membrane Transport Proteins; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D010133:p-Chloroamphetamine; C549477:florbenazine F 18; D013747:Tetrabenazine
Bioconjug Chem. 2007 Sep-Oct;18(5):1612-8
17705553
J Mol Histol. 2008 Oct;39(5):543-51
18791800
Psychopharmacol Bull. 2008;41(2):58-85
18668017
Nucl Med Biol. 2006 Aug;33(6):685-94
16934687
Brain Res Dev Brain Res. 2002 Aug 30;137(2):135-8
12220705
J Pharmacol Exp Ther. 1994 Aug;270(2):713-21
8071864
J Cereb Blood Flow Metab. 2008 Mar;28(3):441-4
18073772
Nucl Med Biol. 2007 Apr;34(3):233-7
17383572
Neuropsychopharmacology. 2009 Mar;34(4):999-1010
18830236
Appl Radiat Isot. 2009 Jun;67(6):1063-7
19339192
Arch Neurol. 2003 Sep;60(9):1223-9
12975287
Brain Res. 1991 Oct 25;562(2):301-5
1685345
Nat Struct Mol Biol. 2009 Jun;16(6):652-7
19430461
Am J Psychiatry. 2004 May;161(5):826-35
15121647
Neuroimage. 2009 Apr 15;45(3):687-93
19211037
J Med Chem. 2000 Aug 10;43(16):3103-10
10956218
J Nucl Med. 2008 Jul;49(7):1171-6
18552132
Biol Psychiatry. 2004 Oct 1;56(7):497-502
15450785
Neuropsychopharmacology. 1998 Jun;18(6):407-30
9571651
J Clin Psychiatry. 2009;70 Suppl 2:25-31
19371504
Brain Res. 1984 Jan 16;291(1):164-7
6199080
J Mol Med (Berl). 2008 Jan;86(1):5-16
17665159
J Med Chem. 2007 Sep 20;50(19):4553-60
17705359
Brain Res. 1987 Nov 3;425(1):85-100
2448003
Brain Res. 2008 Jun 27;1217:185-94
18502405
J Med Chem. 2007 Dec 27;50(26):6673-84
18052090
Neuropathol Appl Neurobiol. 2006 Jun;32(3):296-303
16640648
Synapse. 2000 Dec 15;38(4):403-12
11044887
J Nucl Med. 2009 Sep;50(9):1509-17
19690040
J Psychiatr Res. 2007 Apr-Jun;41(3-4):189-206
16870212
J Neurosci. 2008 Sep 24;28(39):9850-6
18815269
J Med Chem. 2002 Oct 10;45(21):4716-23
12361398
Prim Care Companion J Clin Psychiatry. 2001 Dec;3(6):232-235
15014590
J Neural Transm (Vienna). 2008 May;115(5):721-9
18335163
Nucl Med Biol. 2008 May;35(4):447-58
18482682
J Med Chem. 2008 Jan 24;51(2):271-81
18085744
Brain Res Bull. 1987 Aug;19(2):269-74
3664282
Synapse. 1995 Aug;20(4):316-24
7482291
Brain. 2008 Jan;131(Pt 1):120-31
17956909
Nucl Med Biol. 2007 Apr;34(3):239-46
17383573
Eur J Neurol. 2007 May;14(5):523-8
17437611