INVITED PERSPECTIVE Pancreatic Imaging with 11C- Dihydrotetrabenazine PET: A Perspective

movement disorders (1) have been per- FD influx constant was least affected, Historically, the pancreas has been formed with 3 types of ligands. The first consistent with the tendency of residual a difficult organ to image because of its type is agents that bind to the pre- striatal cells in PD patients to maintain retroperitoneal location and overlying synaptic cellular membrane, such as synaptic dopamine concentrations by visceral organs. Over the past 2 deca- 11C-labeled 2-carbomethoxy-3-(4-flu- upregulation of DOPA decarboxylase des, however, the advent of CTand MRI orophenyl) (2), 11C-methyl- activity and downregulation of the dopa- has allowed clinicians to correlate phenidate (3), and 123I/11C-labeled mine transporter. These findings suggest clinical symptoms with anatomic struc- 2b-carbomethoxy-3b-(4-fluorophenyl)- that although li- ture. These additional anatomic data N-(1-iodoprop-1-en-3-yl)nortropane gands are probably the most sensitive revolutionized the evaluation of many (4). The second type of tracers that tracers for detecting early PD, VMAT2 disease processes of the pancreas, such target the vesicular monoamine trans- ligands may provide the best fidelity as pancreatitis. Unfortunately, these im- porter system includes agents such as for quantifying the number of residual aging modalities do not describe organ 11C-dihydrotetrabenazine, 11C-DTBZ dopaminergic cells. function or easily separate the endocrine (5). The third type is agents that reflect Similar to the loss of dopaminergic from the exocrine pancreas. Specifi- dopamine decarboxylase activity, such neurons in PD and other movement cally, the ability to quantify and mon- as 18F-labeled 3,4 dihydroxypheny- disorders, DM results from either an itor b-cell mass (BCM) is of particular lalanine, 18F-DOPA (1). Recently, the absolute or a relative reduction in BCM scope of monoamine imaging has been that leads to inadequate insulin secre- See page 382 extended to patients with pancreatic tion and hyperglycemia. Currently, pathology. measurement of insulin secretory ca- Although by far the largest number pacity is used as a surrogate measure of importance to the study of diabetes. of clinical and research studies of BCM. Although these measurements Although many investigations have monoamine transport and metabolism are of some value, serum insulin levels focused on this area, to date there is in neurodegenerative diseases have are an imprecise index of BCM. Direct no reliable noninvasive method for used 18F-DOPA, tracers with selectiv- measurement of insulin levels in blood quantifying BCM. ities for the dopamine transporter (2–4, draining from the pancreas is a more Diabetes mellitus (DM) and move- 6–8) and the vesicular monoamine accurate procedure but is invasive and ment disorders such as Parkinson’s transporter, VMAT2 (5,8), have also difficult to perform. Clearly, a noninva- disease (PD) are caused by loss of been used for PET assessment of the sive PET method for evaluating BCM b-cells and dopaminergic neurons, re- status of nigrostrial neurons in PD would be of great value both clinically spectively. Also, several gene products, patients. In a recent study, striatal and for evaluating new therapies for including some that are related to uptake of FD as an index of DOPA treating DM. monoamine transport and metabolism, decarboxylase activity was compared Despite their different embryologic are common to these cell types. Thus, with striatal uptake of 11C-labeled origins, many gene products that dis- tracers that have been used for studying and dihydrotetrabe- play functional similarities are common monoamine physiology in movement nazine, which are tracers of dopamine to b-cells and dopaminergic neurons. disorders may be useful for evaluating transporter and VMAT2 densities, re- Specific examples of these proteins b-cell function in DM. PETand SPECT spectively (9). In this investigation, 3 include DOPA decarboxylase (a key of monoamine transport for the evalu- consecutive PET studies with the 3 lig- enzyme in monoamine biosynthesis), ation of patients with PD and other ands were performed on 35 PD patients monoamine transporters (concentrate and 16 age-matched healthy subjects. monoamines from the extracellular Received Dec. 12, 2008; revision accepted The results demonstrated that the re- space to the cytosol), and vesicular Jan. 29, 2009. For correspondence or reprints contact: Alan J. duction in binding potential (maximum monoamine transporters (concentrate Fischman, Shriners Hospital for Children, 51 number of binding sites divided by the Blossom St., Boston, MA 02114. monoamines into storage granules). E-mail: fi[email protected] dissociation constant) in the PD patients To date, only 2 PET tracers have been COPYRIGHT ª 2009 by the Society of Nuclear 11 Medicine, Inc. was much greater with C-methylphe- used for imaging b-cell function and DOI: 10.2967/jnumed.108.059568 nidate than with 11C-DTBZ, whereas the mass. Although several studies using

PERSPECTIVE ON PANCREATIC IMAGING • Fagan and Fischman 335 the DOPA decarboxylase substrate 18F- in BCM that may be of value in the patients with type 1 DM, compared DOPA have been reported, it remains study and treatment of diabetes. In with controls (P 5 0.001). The de- unclear whether this tracer is of value another study (20), they used 11C- creases in functional binding capacity for imaging normal b-cells in adults. DTBZ to estimate BCM in a rat model and BPND were significantly less (P 5 However, hyperinsulinemia of infancy, of spontaneous type 1 DM (the bio- 0.001) than the near-complete loss of a neuroendocrine condition character- breeding diabetes-prone rat). In longi- stimulated insulin secretion observed in ized by either focal adenomatous hy- tudinal PET studies, they demonstrated type 1 DM. In general, it was concluded perplasia or diffusely increased insulin a significant decrease in pancreatic up- that PETwith 11C-DTBZ can be used to secretion by the pancreas, is clearly take of 11C-DTBZ that anticipated loss quantify VMAT2 binding in the human evaluable with this ligand. Ribeiro et al. of glycemic control. Comparisons of pancreas. However, given the near- (10–12) were the first to report on the standardized uptake values (SUVs) of complete depletion of BMC in long- use of 18F-DOPAPET for differentiating 11C-DTBZ and blood glucose concen- standing type 1 DM (detected by tissue between focal and diffuse hyperinsuli- trations demonstrated that a 65% de- sampling), BPND and functional bind- nemia ofinfancy, and their findings were crease in baseline SUV correlated ing capacity appeared to overestimate subsequently verified by other investi- significantly with the development of BCM. This overestimation may be due gators (13–18). When uptake of 18F- persistent hyperglycemia. These stud- to higher nonspecific binding in pan- DOPA was focal, immunocytochemical ies further supported the notion that creas than in renal cortex. In this analysis of surgical specimens confir- PET-based quantitation of VMAT2 pro- context, it is not clear why the authors med the diagnosis of focal disease. In vides a noninvasive measurement of dismissed skeletal muscle as a reference contrast, when a diffuse pattern of 18F- BCM that may be useful for studying tissue. As correctly pointed out by the DOPAuptakewasobserved,immunocy- the pathogenesis of diabetes and mon- authors, 18F-labeled VMAT2 ligands tochemical analysis revealed distribution itoring therapeutic interventions. In with lower nonspecific binding and the of abnormal b-cells throughout the a PET study of 11C-DTBZ in baboons potential for delayed imaging may be pancreas. In general, the immunocyto- (21), these investigators demonstrated more suitable for the clinical evaluation chemical results closely matched the that most of the injected tracer localized of BCM. PET data and demonstrated colocaliza- to liver and lungs, followed by the in- Although not as yet investigated, 18F- tion of proinsulin and DOPA decarbox- testines, brain, and kidneys. The high- DOPA could also be useful for studying ylase. est estimated absorbed radiation dose BCM in type 1 DM. However, with this These findings clearly establish the was in the stomach wall, and the do- tracer the same issues related to refer- value of 18F-DOPA in the evaluation simetry of doses proposed for human ence tissue selection exist. Moreover, as of hyperinsulinemia of infancy. Unfor- imaging was determined to be safe. in the case of using 18F-DOPA for the tunately, however, 18F-DOPA has sev- In this issue of The Journal of evaluation of patients with movement eral disadvantages as a tracer: a complex Nuclear Medicine (22), the same group disorders, upregulation of DOPA de- procedure is required for its prepara- of investigators extend their studies to carboxylase activity in residual b-cells tion, synthetic yields are poor, and healthy human volunteers (n 5 9) and in patients with long-standing type 1 target-to-background ratios tend to be patients with long-standing type 1 DM DM could diminish the expected re- low. Other tracers, such as ligands that (n 5 6). In this study, VMAT2 binding duction in tracer uptake. Similar con- 11 target VMAT2 (i.e., C-DTBZ), could potential (BPND) was estimated voxel- siderations might exist for studies with be of even greater value for studying wise using renal cortex as reference ligands that are specific for membrane hyperinsulinemia of infancy, and ad- tissue, and the functional binding monoamine transports. Although these ditional studies with these agents are capacity (the sum of voxel BPND · membrane proteins tend to be down- warranted. voxel volume) was calculated as an regulated in movement disorders in PET studies of VMAT2 pathophysiol- index of total pancreatic VMAT2. order to maintain monoamine levels in ogy are in their infancy; however, several Pancreatic BPND, functional binding the synaptic cleft, this may not be the important studies have been published capacity, and stimulated insulin secre- case in pancreatic tissue of patients by the group at Columbia University tion measurements were compared with type 1 DM; in fact, there may be (19–21). In an investigation (19) with between groups. The results of this upregulation. These issues definitely 11C-DTBZ, they demonstrated decreased study demonstrated that mean pancre- require further investigation. radioligand uptake in the pancreas of atic BPND was decreased to 86% of Neurofunctional imaging appears to Lewis rats with streptozotocin-induced control values in type 1 DM (1.86 6 be a new approach that may overcome diabetes, compared with euglycemic 0.05 vs. 2.14 6 0.08, P 5 0.01), and many of the deficiencies found with historical controls. This study sug- BPND correlated with stimulated in- other imaging techniques. The combi- gested that quantitation of VMAT2 sulin secretion in controls but not in nation of 11C-DTBZ and PET appears expression in b-cells with 11C-DTBZ type 1 DM (r2 5 0.50, P 5 0.03). In to represent a noninvasive means to and PET represents a method for non- addition, mean functional binding ca- monitor BCM quantitatively. This tech- invasive longitudinal estimates of changes pacity was decreased by at least 40% in nique may represent a modality to

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