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A Ticket to Ride Peptide Radiopharmaceuticals

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					A Ticket to Ride: Peptide Radiopharmaceuticals
Alan J. Fischman, John W. Babich and H. William Strauss


DivLcion ofNuclear   Medicine, Depamnent ofRadiolo@,         Massachusetts   General Hospital and Depamnent of Radiology,
Ha,vard Medical Schoo4 Boston, Massachusetts



                                                                 The high molecular weight of intact antibodies and even
Over the past three decades, blospecificImagingagents have Fab fragments limits localization diffusion, which usually
evolved from large proteins (I.e., antibodies) to antibody frag requires long intervals between administration and record
merits (i.e., F(ab')2 and Fab fragments) to smaller “molecular diagnosticallyuseful images. In general, the pharmaco
                                                                 ing
                   such
recognitionunits― as Fvfragments, antigen bindingdomain kinetics of lesion localization are poorly matched to the
fragments and small biOlOgically    active peptkies. The smaller physical half-life of the most available and least expensive
size ofthese moleculesconfersdesirable pharmaCOkinetiC     prop radionucide for imaging, @Tc. additional problem is
                                                                                                    An
ertles, such as higher target-to-backgroundratios and faster
blood dearance, that are favorablefor imaging.Molecularengi      the nonspecific accumulationof any IgG at sites of inflam
nearing techniques now permft the peptide to carry the radionu   mation. This observation led to the use of radiolabeled
dide-bindinggroup in ftsstructurewhilemaintaininghigh-afflnfty nonspecific polyclonal IgG for the detection of inflamma
binding to the receptor sIte. An important component to this tion, where it has proven to be equal or superiorto specific
system is the abilftyto radlolabelthese agents withhighspecffic monoclonal antibodies for localizing focal sites of infec
activityusing short-livedradlOnUclldeS,   particularly @rc. Re tion.
                         o
cently, the app1ioa@onf small radiOlabeledbiOlOgICally    active   In the evolution ofbiological diversity, amino acids have
peptides forexternal imagingof a vatietyof biologicalprocesses played a pivotal role as buildingblocks for a vast array of
has received considerable Interest. These applications have molecular signaling, signal transduction and recognition/
ranged fromthe currentwkiespread use ofsomatostatln analogs
for imagingnumeroustypes of tumorsto the developmentof transformationunits (Fig. 1). Amino acids can act as neu
radiolabeledchemotactic peptides for Infectionimaging.In this rotransmitters(i.e., GABA, glycine, glutamate) and pro
review, we willdescdbe many of the parameters for the rational vide a pool of precursorsfor the adrenergic,dopaminergic
development of peptide-based imaging agents, including: and serotonergic neurotransmitters. When assembled into
classes of peptides for Imaging,methods for radiolabelingpep small peptides, amino acids have generated a variety of
tides, current biologicallyactive peptide-based radlopharmaceu hormones, releasing factors, neurotransmittersand neuro
ticais and future prospects for this new technology.             modulators. As larger constructs, amino acids comprise
J NucI Med 1993; 34:2253-2263                                    molecular recognition systems (immunoglobulins and re
                                                                 ceptors) and, when assembled into enzymes, can catalyze
                                                                 nearly the entire lexicon of organic reactions.
                                                                   Some of the unfavorable imaging properties of intact
                                                                 antibodies and conventional fragments might be overcome
                                                                    with smaller specifically designed binding-domain frag
    he high affinity and specificity of antibodies should           ments such as single-chain antigen binding proteins and
make them highly desirablefor diagnostic imaging.Clinical           peptide analogs of hypervariable sequences. In addition,
studies with these agents, however, have often demon                nature has provided avast array of small biologically active
strated limited binding at the target site, relatively slow         peptides with binding affinities that are comparable to or
blood clearance and modest target-to-background ratios.             greater than antibodies. These compounds provide multi
                                                                    pie new avenues for radiopharmaceuticaldevelopment. In
                                                                    the following sections we will discuss classes of peptides
  ReceivedSept 2, 1993;accepted Oct 12, 1993.                       for imaging, methods for radiolabeling peptides, current
  For correspondenceor reprintscon@ Dr. Man J. Aschman, DM@on  of   biologically active peptide-based radiopharmaceuticals and
               D                     M          G              32
NuclearMed@ne, e@rnent of Raclology, easnehus@te eneri Hoepftal,
FrUItSL, oston,MA02114.
       B                                                            future prospects for this new technology.


                            Fischman et al.
Peplide Radiophwmaceuticals•                                                                                           2253
                                                                                     AMINOACES


                                            GABA
                                            Gly    Phe              Histidine
                                            Glu    Tyr              Tryptophan                         polypeptides
                                                                                   dipept1des/fflpept@des                    proteins



                                            GABA   DOPA             Histamine       Thyroxine          ACTh. MSH             Immunoglobullns
                                            Gly    Dopamine         Serotonin       Trllodothyroxlne   CCK. VIP. CRF.
                                            Glu    Noreplnephrlne                   11W                LHRH.NPY.
                                                   Epinephrlne                                                        P.
                                                                                                       CGRP,Substance Etc.




FIGURE 1. Roleofam@oec1dsIntheev                                                 MESSENGERMOLECULE
                   d
olutlonof biological iversity.


CLASSES OF PEP11DES FOR IMAGING                              more favorable imaging properties than sFvs. Unfortu
SIngIs-@haIn Antigen-Binding Proteins                        nately, although peptides derived from hypervariable re
   Recently, it has been suggested that imaging with radio   gion sequences can bind antigenswith similarspecificity to
labeled Fv fragments, which are about 50% smaller than the native antibody, affinity is usually significantly re
Fabs, may minimizemany of the problems associated with duced. However, by using sophisticated methods of mo
the use of intact antibodies and conventional fragments. lecular design, this problem may be surmountable. For
Although these reagents can be produced by fragmentation example, it has been demonstrated that conformationally
of intact antibodies (1), most single-chain bindingproteins constrained and dimeric peptides derived from hypervari
(sFvs) have been prepared by recombinant DNA tech            able loop sequences can bind antigenwith affinitiesthat are
niques (2—6). this approach, the gene sequences coding
               In                                            up to 40-fold higher than linear sequences (11). The corn
for the variable regions of the light and heavy chains of an bination of detailed nuclear magnetic resonance spectros
antibody are linked with a specifically designed oligonucle  copy and molecular modeling has made it possible to de
otide sequence and the construct is expressed in E. coiL In termine the influence of specific amino acid residues on
the finalproduct (25-30 kDa), the carboxyl terminusof the antigen binding (12), allowing the specific design and syn
variable region of the light chain is linked to the amino thesis of peptides with improved binding properties.
terminus of variable region of the heavy chain by a de          One important application of hypervariable region pep
signed 12—20  residue peptide. These proteins have the     tides to in vivo imaginghas already been reported (13,14).
same antigen specificity as the parent antibody. Recent In this study, 16—31     residue analogs of the hypervariable
studies with these sFvs, have demonstrated rapid tumor       sequence of the platelet glycoprotein lib/Illa directed
penetration (4, 7,8). For example, with the pancarcinoma     monoclonal antibody PAC 1.1 were prepared. All of the
antibody (CC49), the time for maximal penetration of sFv peptides contained a tripeptide binding group (RYD or
is 30 müi, while intact IgO requires 48-95 hr to attain ROD) and a metallothionein-derived sequence (KCFCCA)
similar concentrations. Autoradiographic studies compar      for @Tc    labeling. These peptides cleared rapidly and im
ing the penetrationof intact IgO with F(ab)2,Fab and sFvs    ages of fresh thrombi in the jugular veins of rabbits and
revealed that sFvs distnl,ute uniformly in tumors while day-old thrombiin the fernoralveins of dogs were obtained
intact antibodies concentrate in the region of or immedi within 1-2 hr after injection. In control experiments, a
ately adjacent to blood vessels. The distributionsof F(ab)2    @9@c-1abe1ed   nonspecific peptide did not image the
and Fab fragments showed intermediate penetration in a       thrombi.
size-related manner (7,8). When applied to invivo imaging,
sFvs clear from the circulation rapidly (t@ alpha —2--S
                                                        mm          Natural Biologically Active Peptldes
and t@ beta -@-2—5 have low levels of accumulation in
                   hr),                                                In contrast to antibodies, a low and intermediatemolec
background organs and localize rapidly in target tissues            ular weight, naturally occurring peptides may be more
(4,9,10). Although in some cases absolute levels of accu            suitable starting points for radiopharmaceutical develop
mulation in target tissues are lower than with larger frag          ment. Peptides are necessary elements in more fundamen
ments, target-to-background ratios are comparable or                tal biological processes than any other class of molecule.
greater.                                                            For example, peptides function as hormones, neurotrans
                                                                    mitters, neurornodulators, growth and growth inhibition
Hypervarlable Region Peptlde Analogs                                factors and cytokines. Furthermore, in many cases the
   Since antigen binding is largely imparted by the hyper           aflinities of peptides for their receptors are significantly
variable portions of the variable region of antibodies, syn         greater than that of monovalent antibody fragments.
thetic peptide analogs of these regions might have even                The molecularweights ofbiologically active peptides are


2254                                                                                  •       No.    December1993
                                                           The Journalof NudearMedicine Vol.34 • 12 •
extremely diverse; ranging from 3 to 5 residues in TRH, reagents, such as the Bolton-Hunterreagent(N-succinimy
enkephalins and bacterial chemoattractant peptides to over dyl-3-(4-hydroxyphenyl)proprionate).In this case an acti
200 residues in growth hormone. However, in many cases vated aromatic compound (a phenolic conjugate) is radio
molecular recognition sites are restricted to specific areas iodinated, purified and linked to the peptide by acylation of
of the sequence. For example in PTH and ACTH, biolog a free amino group (16).
ical activity is conferred by the N-terminal sequence. Like     The problemof in vivo dehalogenationof radioiodinated
wise, for veiy small peptides, such as TRH and bacterial antibodies led to the investigation of nonphenolic aromatic
chemoattractant peptides, the C-terminus can be extended compounds as radiolabeling reagents, i.e., N-succinimidyl
without significant alterations in receptor binding or bio 5-(iodo)-3-pyridinecarboxylates (SIPC) (17), N-succinim
logical activity. A particular advantage of this focality of idyl-3-iodobenzoate (18) and N-succinimidyl-4-(iodoben
binding domains is the ability to modify sequence regions zoate) (19,20). In most cases, these reagents are prepared
that do not participate in receptor interaction for radiola from trialkylstannylprecursorsand demonstrate improved
being or optimization of biodistribution. For the smaller in vivo stability. This improvementis thought to be related
peptides, these modifications can be performedby the di to theirstructuraldifferencesfrom iodotyrosines/thyroxine
rect chemical synthesis of analogs by methods of solid which are substrates for dehalogenases in a number of
phase or solution synthesis. For largerpeptides (>50 res tissues. The structuralrequirementsfor minimizingin vivo
idues), analogs are more efficiently preparedby molecular dehalogenation (21,22) were evaluated by Zalutsky et a!.
cloning, followed by chemical modification in some cases. Their findings indicate that ring substituents, alkyl chain
                                                             length and the nature of the protein linkage contribute to in
                                                             vivo stability. Zalutsky and colleagues also demonstrated
TECHNIQUES FOR RADIOLABEUNG PEPT1DES
                                                             that octreotide, radioiodinatedwith SIPC, has greater sta
   Numerous approaches are currently available for radio     biity than directly iodinated Tyr-3-octreotide (23). Al
labeling peptides. In general, these techniques are similar though applicationsof these conjugates to peptide radiola
to those used for radiolabelingproteins. However, the im beling have been limited, they hold great promise for the
pact of radiolabelingon biological behavior is frequently future development of stable radioiodinated pharmaceuti
more profoundwith peptides because a smaller numberof cals.
sites are available for labeling and the likelihood of modi     Two radionuclides of iodine, 1@Iand 1311,have been
fying amino acid residues that are essential for biological  used for scintigraphic imaging of peptides (24,25), how
activity is greater. In addition, due to the high potency of ever, the high cost of ‘@I the high radiationdose and
                                                                                         and
many peptides and the low tissue concentrations of their poor image quality associated with ‘@‘I prompted the
                                                                                                       have
receptors, specific activity is often critical.              investigation of other radionuclides. These include @“@Tc
   Methods for radiolabelingpeptides with iodine, techne and “In single-photon imaging and ‘8F, and @Ga
                                                                        for                                 ‘1C
tium, indium, gaffium, carbon and fluorine have been de for PET.
veloped. In the following sections, several examples of
radiolabelingstrategies and their potential pitfalls are dis Technetium
cussed.                                                         The combination of low cost, availability, excellent im
                                                             agingproperties, favorable dosimetiy and high specific ac
lodinatlon                                                                      a
                                                             tivity make @Tclogical choice for peptide labeling.Two
   The technique most widely applied to peptide labeling, approaches, bifunctionalchelates and direct labelingmeth
primarily for in vitro applications, is radioiodination. Pep ods have been described for radiolabeling proteins and
tides may be radiolabeled directly via electrophilic substi peptides with           The
                                                                               @Tc. bifunctional methods employed
tution at reactive aromatic amino acids. Several reagents, DTPA (26), N2S2 (27), N3S (28), BATOS (29), and 6-hy
such as iodogen, are available for direct iodination of re drazinonicotinate(HYNIC) (30) groups as chelates.
active aromatic amino acid residues (15). By optimizing         Direct labeling usually generates free sulfhydiyl groups
reaction conditions, rapid and nearly quantitativelabeling by reductionof disulfidebridges in the protein. In general,
can be achieved. Removal of unreacted radioiodine from this method suffers from two problems: (1) technetium
the reaction mixture can be accomplished by separation frequently forms unstable complexes with the protein; and
techniques such as ion exchange, reverse and normal (2) thereis poorcontrolof the labelingsite(31) Despite
phase chromatography and desalting or size-exclusion these limitations, direct labeling has been useful for pre
chromatography.                                              paring                 antibodies. It is unlikely that direct
                                                                         @@Fc-labeled
   Direct labeling has proven to be so reliable and conve    labeling can be readily extended to smaller peptides be
nient that many peptide analogs have been preparedwith cause most small peptides do not contain disuffides and
Tyr substituted for Phe or added to sequence sites that are peptide structures are often altered by random addition of
not critical for biological activity or receptor binding. the radiolabel. In many peptides, even slight alterations in
Where these modifications are not possible or the oxidizing the ring structurecan result in dramaticalterations in bio
conditions of direct iodination are considered to be too logical activity. In small cyclic peptides like oxytocin and
harsh, an alternative approach is iodination via prelabeled vasopressin, increasingthe size of the ringby a single CH2


                             Fischman at al.
Peptide Radiopharmaceuticals•                                                                              2255
group (replacement of a cysteine by a homocysteine resi apolipoproteinfragment, SP-4 (37) for imagingatheroscie
due) markedly decreases biological activity. In contrast, rosis. The HYNIC and diaminedithiolderivatized chemo
the even smaller structuralperturbationinduced by replac tactic peptides demonstratedbiological activity and recep
mg the S-S moiety by a C-S group results in super active tor binding characteristics similar to the unmodified
analogs. Although the biological activity of somatostatin is peptide.
less sensitive to alterationsin the ring structureand active
analogs with vai@ng numbers of residues in the ring have Indium and Gallium
been prepared, activity is affected by the conformation of       Indium-ill has been used extensively for radiolabeling
the ring residues. Thus, application of thiol-based direct     monoclonal antibodies. The chemistry of this group III
labeling of peptides is almost certain to be unsuccessful. metal and the half-life of this isotope make it ideal for
For example, in an effort to prepare @1Tc@octreotide,          radiolabeling intact immunoglobulins, where imaging stud
Thakur et al. (32) demonstrated that direct labeling via ies are usually performed over intervals of several days.
disuffide reduction, reduced receptor affinityby four orders Rapid and stable labeling is usually accomplished using
of magnitude, confirmingthat alterationsof the cyclic part bifunctionalized derivatives of the polyaminocarboylate
of this peptide can dramaticallyreduce biological activity. chelates EDTA and DTPA (38). DTPA has been used as a
   In addition to disulfides, other functional groups in pep bifunctional chelating agent for radiolabeling a-melano
tides can contribute to @9@c                                                                                 for
                                binding. However, at present cyte-stimulating hormone (a-MSH) with “In imaging
there is no method for predicting the precise geometiy of      melanoma (39), formylated-Met-Leu-Phe chemotactic
chelation or the effects ofradiolabeling on receptorbinding peptides for infection imaging (40), laminin fragments for
or biological activity. Application of this method of direct targeting tumor-associated laminin receptors (41) and atrial
99mTc labeling has been reported for thyrotropin    releasing  natriuretic peptide (ANP) for imaging ANP receptors in the
hormone (TRH) (33) and more recently for a 19 residue kidney (42). Gaffium-68 has been used for radiolabeling
analog of laminin, PA22-2 (34). Biological activity of chemotactic peptides (43) and a somatostatin analog using
    @Tc-TRH considered to be similar to 3H-TRH on the DTPA and desferrioxamine (44), respectively.
             was
basis of chromatographicdata and the time course of ac
cumulation by the pituitaiy. Similarly, biological activity of CURRENTPEPT1DERADIOPHARMACEU11CALS
PA22-2 was implied by altered distribution in the lungs of       The number of biologically active peptides that have
mice with emphysema and melanoma compared to con              potential as imaging agents is so vast that even a list of the
trols. However, in neithercase were receptorbindingstud most promising candidates would span many pages. Al
ies performedto evaluate the effect of labeling on affinity. though applications of these reagents is still in its infancy,
   To overcome the problems associated with direct label many important imaging agents have already been devel
ing, methods have been developed which utilize high-affin o_. Table 1 is a partiallisting of some peptides that have
ity chelates to bind          to
                          @‘Fcspecific sites on peptides.   been radiolabeled and used for in vivo imaging. In the
These chelates can be used in two ways. In the first following sections, we will review the current status of
method, the bifunctional reagent is prelabeled with @9@c radionucide imagingwith biologically active peptides. This
and then conjugated to the peptide, similar to the indirect will be followed by a perspective on future applications.
iodination reagents. If more than one reactive group is
present, multiple species can result. To achieve high spe Somatostatin
cific activities, the unreacted labeling reagent and unla        The peptide that has attracted greatest interest as an
beled peptide must be removed from the reaction mixture. imaging agent is somatostatin. Somatostatin is a small reg
Since these species can be similar in size to the labeled ulatory peptide with a wide spectrum of actions on multiple
peptide, chromatographicpurificationis often difficult. In organs. The most well defined biological activity of soma
the second method, the chelating agent is covalently at tostatin is its inhibitory effect on the secretion of numerous
tached to the peptide prior to radiolabeling. This method hormones, includinggrowth hormone, thyrotropin,insulin,
usually results in a single radiolabeled product, making glucogon, vasoactive intestinal peptide and secretin,
chromatographic separation simpler. Both methods have among others. In addition, receptors for somatostatin are
been highly successful for radiolabelingantibodies and can expressed on a variety of human tumors and their metas
be directly extended to peptides.                             tases (45). In numerous studies, somatostatin and its ana
   Theoretical considerations suggest that indirect methods logs have been shown to inhibit tumor growth (46).
may be preferable. The chemistry of @Tc       labeling is bet    Although the first report of in vivo imaging with a soma
ter defined and more predictablewith this approach, since tostatin analog appeared in 1976 (47), further development
the bioactivity and receptor-bindingcharacteristics of the was delayed because the native peptide is rapidlydegraded
conjugate can be determined before and after labeling.        by plasma and tissue proteases (48) and the role of soma
   Recently, @“@‘Fc-labeling peptides has been tostatin in tumor growth was not identified until years later.
                              of several
reportedusing a variety ofmethods, includingHYNIC (35) Now, somatostatin analogs that are more resistant to bio
and diaminedithiol (36) derivatized chemotactic peptides logical degradation have been developed. One of these
for infection imaging and N2S2 and N3S analogs of the compounds, octreotide, is currently in use for the treat


2256                                                                                â Vol.34 • 12 •
                                                         The Journalof NuclearMed@ine €¢      No.    December1993
                                                                   TABLE I
                                                             Peptide ImagingAgents

                                                  an@nOadd
               PeptideNo.of             reskkiesRadk@nudk1elabelingPrInc@e
     applicationReferencesSomatostatin14lshl,msl,hhhlnTumors47,50,51,55Octreofide8ssGaBacterial


                                                          @‘1c,
     asGalnfe@Ion40,35,43lnterleuldn8791251InfectIon80Endothelin211@lAtherosclerosis81Apo-lipoprotein
            Chem@Ic peptldes3“1ln,


     °°“TcAtherosclerosis37,82Corticotropin
                      fragments18ins1,                                   123@,

                Releasing
     Factor41@ITumors83Ca@oprIl3laj:?
     Hypertension84Atrial
                    Factor28,24@2@l?
          NatriUretIC
     Hypertension42Insulin511311
                                                                         18FDiabetes85,86




ment of a variety of tumors (49,50). The success of cc         have been imagedwith this reagent. Following intravenous
treotide for tumor therapy led to the application of ‘@I injection, radiolabeled octreotide has not been useful for
labeled Tyr-3-octreotide for in vivo tumor imaging (51). imaging CNS tumors when the blood brain barrier is intact.
This radiopharmaceutical retains biological activity and The lack of positive octreotide imagingin some somatosta
binds specifically to somatostatin receptors. In studies with tin receptor-positivetumors (in vitro bindingof somatosta
transplantablepancreatictumors (CA 20948)in rats, it was tin-14, somatostatin-28) but not octreotide could be related
demonstrated that in vivo imaging is rapid and can be to selective expression of differentreceptor subtypes (59).
blocked with unlabeled peptide. These results were yen         This problem may be addressed by developing radiola
fled in patients with tumors that express somatostatin re beled analogs with broader receptor specificity.
ceptors (52). After injection of the radiolabeled peptide,        Despite the success of radiolabeledoctreotide for tumor
about 50% of the radioactivity is cleared from the blood       imaging, enthusiasm must be tempered with caution. Al
pool within 2 min and simultaneous accumulation in the thoughblockade oftumor uptakehas been demonstratedin
tumor occurs. In most cases radioactivity is retained in the animal models and positive imaging in patients is well cor
tumor for 24—48hr and residual activity is cleared by the    relatedwith cx vivo measurementsof receptor expression,
liver through the biliary system into the intestinal tract
(53).                                                                Pftultary Adnoma                   Livr metastassa
                                     has
   Although ‘@I-1@yr-3-octreotide proven to be useful
for tumor imaging, several problems prevent widespread
                              is
application: (1) pure ‘@I not widely available and a
complicated procedure is requiredfor radiolabeling;(2) the
                       (13
short half-lifeof ‘@I hi) hampers delayed imaging;and
(3) accumulation of radioactivity in the liver, gallbladder               I                                                I
and 0! tract complicate the imaging of tumors in the ab
domen. To minimize these problems, “In-labeled TPA   D
octreotide was developed. The receptor binding and bio
logical activity of “InDTPA octreotide are similar to
those of octreotide (54). About 90% of this radiopharma
ceutical is cleared by the kidneys within 24 hr after injec
tion. Compared with ‘@I-octreotide,      hepatic and biliaiy
                                            is
accumulationof “In-DTPA-octreotide much lower; 2%
versus 40% at 4 hr after injection (55). The differences in
clearance of these two forms of octreotide are probably
related to differences in hydrophilicity. Indium-111-DTPA
octreotide is definitely a better agent for imaging abdominal
tumors, but tumor localization could still be obscured in
some situations, particularlyat late imaging times (56).
   Indium-111-DTPA-octreotide is useful for detecting tu            Metastaticcarcinoid           Mdullary  carcinoma  Thyroid

mors that express somatostatin receptors (Fig. 2) (57,58). FIGURE 2. Examplesoftumors thathave been successfuly Im
Table 2 summarizes the range of peripheral tumors that                    w     odre@de.
                                                                        — @@olabsied
Peptide RadiOpharmaCeuticalS                      etal.                                                                2257
                                                           TABLE 2
                                   DetectionFrequenoesof HumanTumorswith1111n-Octreotide
                                                                     vivo111Ir@,@                             receptor
                                                                                                          vitro
                        t
                  TumorypeIn
           autoradiographyPituitary                                  ImagingIn
                                                            octrectide
             adenomasGH4/4
             (100%)45/46(98%)TSH2/2
             (100%)2/2(100%)Inactiveem
           (67%)6/15(40%)Endocrine
                    pancreastumors18/21
           (86%)31/35(89%)Carcinolds37/39
           (95%)54162(88%)Paragangllomas29/31
           (94%)11/12(93%)Pheochmmocytomas2/5
           (40%)38/52(73%)Medulary
                    th@d cardinoma8/12
           (67%)10/26(38%)Lung
             @m@sSCLC5/8
             (63%)417(57%)NOnSCLC3/4
           (75%)0/17(0%)Neuroblastoma5/5
           (100%)15/23(65%)MeriIn@1
           (100%)54/55(98%)Glial                             1/1 1
             tumorsAstrocytomas4/4(100%)14/17(83%)Glioblastomas0/2

           (0%)1/45(2%)Merkel
                 celltumors4/5
           (80%)—Breast
                 carcinoma39/52
           (75%)33172(46%)Adenocardnoma5/29
           (17%)6165(6%)LymphomaHodgldns3/3

             (100%)2/2(100%)NonHodgklns10/1
  (91%)26/30(87%)Adapted                                        1


          from         55                      d               f different
              references and58. InvlvoandInvitro atawereobtainedrom          o
                                                                        groups fpatients.



there is limited data on the effect of pretreatment with             technique. In this regard, it should be compared to other
unlabeled peptides on imaging of human tumors. This is               nonspecific imaging agents such as 67Ga-citrate and l8@rj@
important because a significant amount of localization               PET. Clearly, radiolabeled octreotide has many advan
could be due to nonspecific increases in tissue permeabil            tages over gallium. However, due to the high resolution
ity, particularlyat early imagingtimes. Only blocking stud           and sensitivity of PET and the quantitative nature of the
ies can determine the fraction of localization that is truly         measurement, FDG is a more formidable competitor. In
receptor mediated. Recently, it has been reportedthat pre            fact it has recently been demonstrated that “In-DTPA
treatment with therapeutic doses of octreotide decreased             octreotide is considerably less sensitive than ‘8FDG for
the level of accumulationof “11n-DTPA-octreotide   in nor          detecting a variety of tumors (6Z63).
mal tissues but had minimal effect on tumor localization
(60). These results could be explained in several ways:              Chwiotactlc Peptides
                                                                       The development of reagents for the rapid and accurate
  1. The circulating concentrations of unlabeled drug
                                                                     delineation of focal sites of infection is an important issue
     were significantlylower than the blocking doses that
                                                                     in current nuclear medicine practice. Currently, the most
     were used in animal experiments and thus may not
                                                                     commonly used radiopharmaceuticals, 67Ga-citrate and ra
     have been sufficient for receptor saturation.
                                                                     diolabeled leukocytes, require at least 24 hr between injec
  2. It is possible that pretreatment with octreotide re
                                                                     tion and imaging In addition, radiolabeled cells require
     sulted in upregulationof somatostatin receptors This
                                                                     complicated labeling procedures that are associated with
     effect has been reported for GH@C1      pituitary cells
                                                                     potential dangers of blood handling. The interval between
     (61).
                                                                     injection and lesion detection and the inconvenience and
   These results point out the importance of carefully con           potential hazards of in vitro cell labeling could be reduced
trolled blocking studies Such studies are critical if cc             by radionucide imagingwith small molecules that bind in
treotide scintigraphyis to proceed for an imagingtechnique           vivo to both circulating granulocytes and leukocytes al
to a method for the in vivo quantificationof somatostatin            ready present at the site of inflammation. Due to their high
receptors.                                                           affinity for inflammatory   cells and very low molecular
   As more and more tumors are shown to express soma                 weight, analogsofFor-MLF are particularlyappealingcan
tostatin receptors, octreotide scintigraphy is rapidly being         didates for this application. The parent peptide of this
transformed from a specific to a nonspecific tumor imaging           series is a bacterial product that initiates leukocyte chemo


2258                                                                                    Vol.34 • 12 •
                                                           The Journalof NuclearMedidne•      No.    December1993
@                , I                                   I' @/

                                                                  tic peptides to infection imagingwas due to a combination
                                                                  of limitations in radiolabelingtechnology and a potentially
                                                                  adverse side effect of the compounds. The radiolabeling
                                                                  methods used in the early studies yielded radiopharmaceu
                   @.
                 @ly•                                           ticals of relatively low specific activity and pharmacologi
                                                                  cal concentrations of peptide were required for imaging.
                                                                  These doses of peptide were shown to produce profound
@                 .       @.                                      transient reductions in peripheralleukocyte levels in rab
                                                                  bits and dogs (72—75).
                                                                    Since previous structure-activity studies have estab
@           List.                                                lished that the C-terminus of For-MLF can be extensively
                                                                 modified without significantly altering bioactivity or recep
                                                                 tor binding, this is an ideal site for radiolabeling.Recently,
                                                                 we demonstrated that C-terminal DTPA derivatized che
                                                                 motactic peptide analogs can be prepared by standard
                          Tc          .      In                  methods of solid phase peptide synthesis and radiolabeled
                                                                 with “In  (40). In these studies, four DTPA derivatized
    FIGURE3. Representative     dual-photon        of
                                           Images a rabbitwith chemotactic peptide analogs were synthesized, evaluated
                 TheImageswereacquiredat3 (upperimages)and 17
    mildinfection.
    (lower images) rafter
                   h       co-injection
                                     ofes@@@Tc@Iabeled           for
                                                      chemotactic in vitro bioactivity and receptor binding, and radiola
    peptide 1111n-WBCs.
            and              Onlyanterior Images areshown.  The beled with “In.   Biodistributionwas determinedin normal
                                           ofthe radlopharmaceu rats and localization at sites of E. coil infection was deter
    animalswereInfected24 hr beforeInjection
    deals.                                                       mined by scintillation camera imaging from 5 mm to 2 hr
                                                                 after injection. All of the peptides maintained biological
                                                                 activity (EC@for 02-production by human PMNs: 3-150
    taxis by binding to high affinityreceptors on inflammatoiy nM) and the ability to bind to the oligopeptide chemoat
                   These receptors are present on both PMNs tractant receptor on human PMNs (EC@ for binding:
    cells (64—66).
    and mononuclear phagocytes. As cells respond to a 7.5—50           nM); biological activity and receptor binding were
    chemoattractant signal, the affinity of the receptors de     highlycorrelated(r = 0.99). In vivo, biodistnibutionsof the
    creases and additional receptors are expressed, until the peptides were similar, with low levels of accumulation in
    site of inflammation is reached (67—69).  Many synthetic the heart, lung, liver, spleen and 01 tract. With all the
    analogs of For-MLF bind to neutrophils and macrophages peptides, excellent images of infection sites were obtained
    with equal or greater affinitycompared to the native pep within 2 hr after injection.
    tide (64,65,70).                                                Although these studies indicated that “In-labeledhe c
       Like somatostatin receptor imaging, current applications motactic peptide analogs are effective agents for the exter
    of radiolabeled chemotactic peptides to in vivo imaging is nal imaging of focal sites of infection, the rapid infection
                                     Although the first use of a localization and short biological half-life of these agents
    also a case of “re-discoveiy.―
                                                                              a
    radiolabeled chemotactic peptide for abscess localization makes “In suboptimal radionucide forlabeling. Clearly,
    was reported in 1982 (71), further development was de 99'@Tc        would be a more appropriate nucide. A new reagent
    layed until recently. The delay in applicationof chemotac for radiolabelingproteins with @“@Tc      via hydrazino nicoti


                                                          .--




       E


       S
       @0   [X


      I,


@           T                                                                                                of
                                                                                       FiGURE4. Biodistributlona
                                                                                           chemo@lc peptide
                                                                                       baled                      Each
                                                                                                          Inrabbits.
                                                                                                        s.e.m.forsixanimals.
                                                                                       polntis the mean±


                                 Fsschmanet al.
    Peptide Radiopharmaceuticals•                                                                                      2259
                          TABLE 3                             pared to “In-WBCs    (8.1:1). This differencewas primarily
          Species Specificityof ChemotacticPeptides           due to greateraccumulationof the @Tc-labeled       peptide in
                                           and            In  infected muscle rather than differences in accumulation in
                                       spleen     Ieukocyte   normalmuscle. The biodistributionof the @Tc        peptide in
   SpeciesInfection uptakeLiver        uptakeRedUctIOn
  levelsRats+—+—Rabbits++++Dogs+—++MonkeysNT-++NT
                ImagingLung                                   rabbits is shown in Figure 4. In contrast to earlier studies
                                                              with chemotactic peptides that resulted in transientleuko
                                                              penia, the high specific activity peptide did not reduce the
                                                              peripheral WBC count in these rabbits. Similar experi
                                                              ments in dogs yielded comparable results (unpublishedre
                                                              sults).
             t
       = not ested.                                              It is interestingthat although @Tc-labeled    chemotactic
                                                              peptides are excellent infection imaging agents in all spe
                                                              cies tested, importantdifferences in in s'ivo bioactivity and
                                                              biodistnibution were observed (Table 3, Fig. 5). For exam
namide (HYNIC) derivatized epsilon amino groups of ly pie, although significant concentrations of radioactivity
sine residues (30) was recently reported. This method of were detected in the liver and spleen of all species, high
preparing high specific activity @‘Fc-labeled   compounds levels of pulmonary activity were seen only in rabbits.
was applied to the chemotactic peptide analogs, where Also, the rat is the only species that we studied that is
specific activities >20,000 mCi/@molewere prepared(35). insensitive to the effect of peptide on peripheralleukocyte
These high specific activity peptides retained their biolog levels.
ical activity and binding affinity, and demonstrated imaging
characteristicsin rats that were similarto the “In-labeled
peptides.                                                     FUTURE APPUCATIONS
   Since the current standardfor infection imaging is radi       Application of radiolabeled biologically active peptides
olabeled white cells, a comparison of “In-labeled    leuko for imaging is in its infancy. These molecules offer major
cytes to                 p
               @Tc-labeledeptides was performed in infected advantages for imaging including: pharmacokinetic proper
rabbits. The animals were imaged at 3, 6 and 17 hr after ties resulting in rapid localization and blood clearance;
injection Sites of infection were well visualized with both ability to synthesize analogs with specific biological, label
radiopharmaceuticals and the biodistributions were sur        ing and biodistribution properties; and available ap
prisingly similar (76). Figure 3 shows representative dual    proaches for high specific activity labelingwith short-lived
photon images of an animalwith mild infection. In the early radionucides. This combination of early specific imaging
images, both agents showed a high level of accumulationin with high photon flux radiopharmaceuticals can lead to
the lungs, bone marrow, liver and spleen (the characteristic images with better resolution, and hence improved diag
pattern for labeled WBCs). In the late images, pulmonary nostic accuracy. In additionto the agents described above,
activity decreased for both radiophannaceuticals. From anothergroupofcandidate peptides for imaginginclude the
region of interest (ROI) analysis, the T/B ratios were 3.63 growth factors (77). Receptors for these peptides are highly
± 0.37,5.66 ±  1.97and10.47±     2.78for the @“Tc-peptideexpressed in tumors and following injury. This group of
and 2.41 ±1.15, 1.76 ±0.23 and 5.45 ±2.37 for “In agents includes: TOF-beta (tumor growth factor) to iden
WBCs at 3, 6 and 17 hr afterinjection. The average ratioof tify receptors associated with neural injury (particularly
T/B ratios [(TfB)Peptide/(TIB)WBC] was 2.20 ±1.06. TIB associated with demyelination); FGF (fibroblast growth
ratios calculated from direct tissue sampling were signifi factor), to accelerate vessel growth into areas of injury
cantly (p < 0.01) higher for @°@Tc     peptide (33.6:1) corn (78); PDGF (platelet derived growth factor) to identify sites




                                                      Receptor
                                                                            Peptide            Tether           Label



FiGURE5. Schematlcdlagramofapep
   r              Inwhich
tide adiopharmaceutlcal receptor
                                         can
binding, radlolabeling and biOdlstribUtlOn
                  optimize inical tli
beIndMduallyalteredtO    d      u
fty.


2260                                                                                •       No.    December1993
                                                        The Journalof NuclearMedicine Vol.34 • 12 •
of vascular injury and possibly areas of resetnosis; and                                characterizationof a high affinityanti-fluoresceinsingle-chainantibody.I
EGF (epidermalgrowth factor) as a markerfor gliioma. In                                 Bid Client1990;265:18615—18620.
                                                                                     7. Yokota T, Milenic DE, Whitlow M, Schlom J. Rapid tumor penetration of
addition to the growth factors, other substances such as                                                                                   forms.Cancer
                                                                                        a singlechainFvand comparisonwithotherimmunoglobulin
Np-Y (neuropeptideY) or CCK (cholecystokinin) could be                                  Re.c 199252:3402-3408.
labeled to examine the satiety center of the brain.A recent                                  1,      DE,     M,     J.          autoradio
                                                                                     8. Yokota Milenic Whitlow Schiom Quantitative
                                                                                        graphic studies of tumor penetration of a single-chainFv (sFv), Fab',
survey of the literature identified over 300 receptors and                              F(ab')2, and intact monoclonalIgG [Abstractj.ñucAwwMeetAntAssoc
their agonists. Each of these are potential candidates for                              CancerRes 199233:2044.
examination with a peptide-based radiopharmaceutical.                                9. LarsonSM.Improved                   with
                                                                                                             tumortargeting radiolabeled,              sin
                                                                                                                                             recombinant
                                                                                        gle.chain,antigenbindingprotein.JNatI Cancerlnst 1990;82:1173-1174.
   As Figure 5 illustrates, it may be possible to specifically                                      M          DJ,        R,
                                                                                    10. Nedelman A, Sheally BOU1in Ctal. Rapidinfarctmaging ith i     w
design radiopharmaceuticalswith independent manipula                                                           a
                                                                                        technetium-99m-labelednthnyosinrecombinantsingle-chainFv: evalua
tion of segments of the reagent that control binding, radi                              tion in a caninemodelofacute myocardialinfarction.INuclMed 1993;34:
olabeling and biodistnibution.With this approach, radiola                               234-241.
                                                                                    11. Williams                     1,
                                                                                                  WV, Kieber-Einmons VonFeldtJ, GracesMT, WeinerDO.
beling groups and peptide units can be independently                                    Designofbioactive pe@es based on antibodyhypewariableregionstruc.
coupled to a relatively low molecularweight “tether.―By                             litres. Developmentof conformationallyconstrainedand dimericpeptides
using specific protecting group strategies, the peptide can                             with enhancedaffinity.IBid C/tern1991;15:5182-5190.
                                                                                                    L,                  J.            the
                                                                                    12. Riechmann WeillM, Cavanagh Improving antigenaffinityof an
be coupled via amino acid residues that arenot essential for                            Fv-fragmentby proteindesign.IMO1Bid 1992;20:913-918.
binding. Also by coupling multiple radiolabelingmoieties                                                    R,          M,
                                                                                    13. KnightLC, Radcliffe Kollniann et at.Thrombusmagingi       with @Fc
(such as hydrazino nicotinamidegroups) to a single site on                              syntheticpe@es reactivewith activatedplatelets[Abstract).INuci Med
                                                                                        199031:757P.
the tether, extremely high specific activities can be                               14. KniajuLC.Scintigraphic                              t
                                                                                                                methodsfordetectingvascularhrombus.  INuci
achieved. Furthermore,the size, charge and polarityof the                               Med 1993;34(suppl):554-561.
tether can be varied to optimize biodistnibutionfor specific                        15. Fracker PJ, Speck JC. Protein and cell membrane iodination with a spar
applications. In some cases, it mightbe possible to dramat                                                                                               Bk,.
                                                                                        ingly soluble chioramide 1,3,4,6-tetrachloro-3a.6a-diphenylajycouril.
                                                                                        diem Biophys Res Commun 1987;80:849-857.
ically increase binding affinity by clustering multiple pep                         16. BoltonAM,Hunter    RM.Thelabelingofproteins   tohighspecificlabelingby
tide units at a single site. For example, in the case of                                                 c          acylatingagent.BIOC!ZemI
                                                                                        conjugationto 125! ontaizthtg                         1973;133:529-539.
chemotactic peptides, tetramenicanalogs have been shown                             17. Gargpiç GargS,Za1tUSkyMR.     N-succinnnidyl5-(fflalkylstannyl)-3-pyridi
                                                                                        necarbcxylates:a new class of reagentsfor protein labeling.Bioconjugate
to have extremely high affinities(79).                                                  Client1991;2:50-56.
   Another method for improving affinity involves the use                                     M Narula S.A method
                                                                                    18.Zalutsky R1   A                              of proteins
                                                                                                                fortheradiohalogenation
of multiple binding determinants. For example, using                                    resultingin decreasedthyroiduptakeofradioiodine.Aj@lRadiatIsot 1987;
                                                                                       38:@O51—@055.
monoclonal antibody technology, antibodies to specific cx                                   D
                                                                                    19.Wilbur S, Hadley           MD,et al. Development a stable
                                                                                                       SW,Hylarides                  of
ternal domains on peptide receptors can be prepared.                                    radioiodinating reagent to label monoclonalantibodiesfor radiotherapyof
Some of these antibodies might bind to the receptor at                                  cancer.JNuclMed 1989;30:216-226.
                                                                                                A                                    n-succinimidyl ara-ildoben
                                                                                    20. KhawLi , KassisA. Synthesisof ‘@‘I-lsbeled             p
locations that are different from where the native ligand                               zoate for use in radiolabelingantibodies.Nuc Med Bid 1989;16:727-733.
binds. By preparing a conjugate that contains both the                                                 G
                                                                                    21. Vaidyanathan , Zalutsky    MR.Protein                   observations n
                                                                                                                               radiobaloganation:            o
native peptide and a binding site sequence of such an                                           of            esteracylationgentsBioConj
                                                                                        thedesign N-succinimidyl           a                1990
                                                                                                                                       C/tern
                                                                                        1:269-273.
antibody, cooperative high affinity binding might be                                                  AffleckDJ, Zalutsky MR. Radioiodinationof proteins
                                                                                    22. Vaidyanathan @,
achieved.                                                                                                                    I LabeledCpdcand Ra
                                                                                        usingN-su@inünidyl-4-hydrctcy-3-iodobenzoate.
   Clearly, the methods for assembling peptides into effec                             dic@phann1993;32:378—380.
                                                                                    23. Garg5, GargPK, ZalutskyMR. Acylationreagentsfor the radiohalogena
tive imaging agents is as vast as the number of peptides                                tion of peptides.ILabeled Cpds and Radiophann 1993;32:212-213.
with importantimagingapplications. With the close coop                              24. DozioN, MicossiP, Oalimberti0, et al. In vivo demonstrationof insulin
eration of biologists, biochemists, radiochemists and clini                                                             insulinand scintigraphic
                                                                                        receptordefectwith ‘2'I-lsbeled                       scanningin severe
                                                                                        insulinresistance.Diabetes Ca,@1992;15:651-656.
cians, peptide-based imaging agents promise to be among                             25. BourgeoisP, FruhlingJ, Langohr M, Ct al. Dynamic ‘31I@l@J        insulin
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                                                                                                             D                F
                                                                                    27. RaoTN,Adhikesavalu , CainennanA, ritzbergAR.      Technefium(V) nda
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                            Flschman et al.
Peptide Radkpharmaceudcals •                                                                                                                         2263

				
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Description: A Ticket to Ride Peptide Radiopharmaceuticals